Methods and compositions for daily ophthalmic administration of phentolamine to improve visual performance

ABSTRACT

The invention provides methods, compositions, and kits containing phentolamine for improving visual performance. In particular, the invention provides improvement in visual performance, such as improvement in visual acuity, by daily ophthalmic administration of a phentolamine solution to an eye of a patient at or near the bedtime of the patient for an extended duration while minimizing the occurrence of adverse side effects, such as eye redness during the patient&#39;s waking hours.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/754,965, filed Jun. 30, 2015, which is a continuation of U.S. patentapplication Ser. No. 14/169,342, filed Jan. 31, 2014, now U.S. Pat. No.9,089,560, which claims the benefit of and priority to U.S. ProvisionalPatent Application Ser. No. 61/759,542, filed Feb. 1, 2013, the entirecontents of each application are incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

The invention provides methods, compositions, and kits containingphentolamine for improving visual performance. In particular, theinvention provides improvement in visual performance, such asimprovement in visual acuity, by daily ophthalmic administration of aphentolamine solution to an eye of a patient at or near the bedtime ofthe patient for an extended duration while minimizing the occurrence ofadverse side effects, such as eye redness during the patient's wakinghours.

BACKGROUND

Deficient visual performance can have a significant negative impact on apatient's quality of life, affecting, for example, ability to performnormal daily tasks, perform at school, and perform at work. Theinability to see clearly can impact people during normal daylightconditions and during low-light conditions, such as nighttime. One typeof vision problem experienced by a substantial number of patients ispoor night vision. The inability to see clearly under such low lightconditions can make it difficult and/or dangerous for a patient tooperate a motor vehicle at nighttime. Patients that are more likely toexperience night vision problems include those suffering from nightmyopia, have an equatorial cortical cataract, have had surgery to insertan intraocular lens, and/or underwent LASIK surgery. Exemplary symptomsof poor night vision include glare, halos, starburst, ghosting patterns,and/or poor depth perception.

Certain therapies have been described for improving visual performance.For example, the Bernstein Center for Visual Performance offers programsthat utilize visual aids, such as puzzles, stereoscopes, and eyeglasses, designed to improve visual performance. U.S. Pat. No. 6,291,498describes the use of phentolamine to, for example, optimize pupil sizein a patient. However, one adverse side effect of phentolamineadministered to the eye of a patient is eye redness. The need exists formethods and compositions that provide the patient with improved visualperformance during the patient's waking hours, while minimizing theoccurrence and/or degree of eye redness caused by phentolamine duringthe patient's waking hours.

The present invention addresses the aforementioned need for methods andcompositions for achieving improved visual performance while minimizingthe occurrence and/or degree of eye redness caused by phentolamineduring the patient's waking hours, and the invention provides otherrelated advantages.

SUMMARY

The invention provides methods, compositions, and kits containingphentolamine for improving visual performance. One aspect of theinvention provides improvement in visual performance, such asimprovement in visual acuity, by daily ophthalmic administration of aphentolamine solution to an eye of a patient at or near the bedtime ofthe patient for an extended duration while minimizing the occurrence ofadverse side effects, such as eye redness during the patient's wakinghours. The methods and compositions provide particular benefits topatients suffering from reduced visual performance during normaldaylight conditions and during low light conditions, such as nighttime.One benefit of administering the ophthalmic solution at bedtime is thatthe patient desirably will not experience any significant eye rednessduring waking hours. Another benefit provided by the invention is thatimproved visual performance is achieved without diminution in efficacyof the phentolamine solution even after daily administration for anextended period of time. Exemplary aspects and embodiments of theinvention are described below.

Another aspect of the invention provides a method of improving visualperformance in a patient while minimizing eye redness during thepatient's waking hours. The method comprises administering to an eye ofa patient once per day at or near the bedtime of the patient for atleast five consecutive days a daily dosage of phentolamine or apharmaceutically acceptable salt thereof sufficient to provide improvedvisual performance for at least twenty hours, wherein the patientexperiences an increase in eye redness of no more than two gradesmeasured using the CCLRU Redness Grading Scale during the patient'swaking hours compared to the patient's level of eye redness withoutreceiving said dosage. Eye redness is an undesirable side effectexperienced by certain patients when phentolamine is administered to theeye. The present invention provides improvement in visual performanceduring the patient's waking hours, while minimizing eye rednessexperienced by the patient during the patient's waking hours.

Another aspect of the invention provides a method of reducing pupildiameter in a patient while minimizing eye redness during the patient'swaking hours. The method comprises administering to an eye of a patientonce per day at or near the bedtime of the patient for at least fiveconsecutive days a daily dosage of phentolamine or a pharmaceuticallyacceptable salt thereof sufficient to reduce pupil diameter for at leasttwenty hours, wherein the patient experiences an increase in eye rednessof no more than two grades measured using the CCLRU Redness GradingScale during the patient's waking hours compared to the patient's levelof eye redness without receiving said dosage. Reduction in pupildiameter is contemplated to provide improvements in visual performance.

Another aspect of the invention provides a method of reducing anaberrant focus of scattered light rays in a patient's eye whileminimizing eye redness during the patient's waking hours. The methodcomprises administering to an eye of a patient once per day at or nearthe bedtime of the patient for at least five consecutive days a dailydosage of phentolamine or a pharmaceutically acceptable salt thereofsufficient to reduce aberrant focus of scattered light rays in apatient's eye for at least twenty hours, wherein the patient experiencesan increase in eye redness of no more than two grades measured using theCCLRU Redness Grading Scale during the patient's waking hours comparedto the patient's level of eye redness without receiving said dosage. Thereduction in aberrant focus of scattered light rays in a patient's eyeis contemplated to provide an improvement in visual performance.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 is a line graph showing the percentage of eyes that showed atleast a 50% improvement in contrast sensitivity relative to baselinefollowing daily administration of phentolamine mesylate, as described inExample 1 where the patient's contrast sensitivity was measured on days1, 4, 8, and 15 of the study two hours after administration of thatday's dose.

FIG. 2 is a line graph showing the percentage of eyes that showed atleast a 50%, improvement in contrast sensitivity relative to baselineprior to daily administration of phentolamine mesylate, as described inExample 1 where the patient's contrast sensitivity was measured on days1, 4, 8, and 15 of the study prior to administration of that day's dose.

FIG. 3 is a line graph showing the percentage of eyes that showed atleast a 50% improvement in contrast sensitivity relative to baselineprior to daily administration of phentolamine mesylate, as described inExample 1 where the patient's contrast sensitivity was measured on days1, 4, 8, 15, and 32 of the study prior to administration of that day'sdose.

FIG. 4A is a bar graph showing the percentage of eyes with at least a50% improvement in contrast sensitivity after the last dose ofphentolamine mesylate during the second period of the study, asdescribed in Example 1.

FIG. 4B is a bar graph showing the percentage of eyes with at least a10% reduction in pupil diameter after the last dose of phentolaminemesylate during the second period of the study, as described in Example1.

FIG. 5 depicts multiple line graphs showing eye redness in patientsbefore and after receiving phentolamine mesylate on days, 1, 4, 8, and15 of the study, as described in Example 1.

FIG. 6 is a bar graph showing the percentage of eyes with an improvementin mesopic low contrast visual acuity (mLCVA), as described in Example1, where eyes received either placebo (P) or a 1% (w/v) phentolaminemesylate solution.

FIG. 7 is a bar graph showing the percentage of eyes with an improvementin photopic high contrast visual acuity (pHCVA), as described in Example1, where eyes received either placebo (P) or a 1% (w/v) phentolaminemesylate solution.

FIG. 8 is a bar graph showing mean Visual Functioning Questionnaire(VFQ) Improvement Score on day 32 of the study in subjects with ≥50% vs.<50% improvement in contrast sensitivity, as described in Example 1,where the abbreviation “CPD” refers to cycles per degree.

FIG. 9 is a line graph showing the reduction in pupil diameter relativeto baseline after daily administration of phentolamine mesylate, asdescribed in Example 1 where the patient's pupil diameter was measuredon days 1, 4, 8, and 15 of the study two hours after administration ofthat day's dose.

FIG. 10 is a line graph showing the reduction in pupil diameter relativeto baseline prior to daily administration of phentolamine mesylate, asdescribed in Example 1 where the patient's pupil diameter was measuredon days 1, 4, 8, and 15 of the study prior to administration of thatday's dose.

FIG. 11 depicts exemplary eye redness as measured according to (1) theCCLRU Redness Grading Scale, and (2) the NYX-001 Redness Grading Scaleused in Example 1.

FIG. 12 is a line graph showing eye redness score for patients 0.5, 1,2, 4, and 8 hours after receiving placebo or a phentolamine mesylatesolution, as described in Example 2.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides methods, compositions, and kits containingphentolamine for improving visual performance. One benefit of theinvention is that it provides improvement in visual performance, such asimprovement in visual acuity, during the patient's waking hours whileminimizing the occurrence of adverse side effects, such as eye rednessduring the patient's waking hours. Another benefit is that the inventionprovides improved visual performance without diminution in efficacy ofthe phentolamine solution even after daily administration for anextended period of time. The methods and compositions provide particularbenefits to patients suffering from poor visual performance duringnormal light conditions and during low light conditions, such asnighttime. Various aspects of the invention are set forth below insections; however, aspects of the invention described in one particularsection are not to be limited to any particular section.

Definitions

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below.

The terms “a,” “an” and “the” as used herein mean “one or more” andinclude the plural unless the context is inappropriate

As used herein, the term “patient” refers to organisms to be treated bythe methods of the present invention. Such organisms preferably include,but are not limited to, mammals (e.g., murines, simians, equines,bovines, porcines, canines, felines, and the like), and most preferablyincludes humans.

As used herein, the term “effective amount” refers to the amount of acompound sufficient to effect beneficial or desired results. Unlessspecified otherwise, an effective amount can be administered in one ormore administrations, applications or dosages and is not intended to belimited to a particular formulation or administration route. As usedherein, the term “treating” includes any effect, e.g., lessening,reducing, modulating, ameliorating or eliminating, that results in theimprovement of the condition, disease, disorder, and the like, orameliorating a symptom thereof.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for therapeutic use in vivo or exvivo.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions (e.g., such as an oil/wateror water/oil emulsions), and various types of wetting agents. Thecompositions also can include stabilizers and preservatives. Forexamples of carriers, stabilizers and adjuvants, see Martin inRemington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton,Pa. [1975].

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention. As is known to thoseof skill in the art, “salts” of the compounds of the present inventionmay be derived from inorganic or organic acids and bases. Examples ofacids include, but are not limited to, hydrochloric, hydrobromic,sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic,lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic,citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic,naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids,such as oxalic, while not in themselves pharmaceutically acceptable, maybe employed in the preparation of salts useful as intermediates inobtaining the compounds of the invention and their pharmaceuticallyacceptable acid addition salts.

Examples of bases include, but are not limited to, alkali metals (e.g.,sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄ alkyl, andthe like.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate (mesylate), 2-naphthalenesulfonate, nicotinate,oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate,pivalate, propionate, succinate, sulfate, tartrate, thiocyanate,tosylate, undecanoate, and the like. Other examples of salts includeanions of the compounds of the present invention compounded with asuitable cation such as Na⁺, NH₄ ⁺, and NW₄ ⁺ (wherein W is a C₁₋₄ alkylgroup), and the like.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

The term “alkanoate” is art-recognized and refers to alkyl-C(O)O⁻.

The term “alkyl” is art-recognized, and includes saturated aliphaticgroups, including straight-chain alkyl groups, branched-chain alkylgroups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkylgroups, and cycloalkyl substituted alkyl groups. In certain embodiments,a straight chain or branched chain alkyl has about 30 or fewer carbonatoms in its backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀ forbranched chain), and alternatively, about 20 or fewer. Likewise,cycloalkyls have from about 3 to about 10 carbon atoms in their ringstructure, and alternatively about 5, 6 or 7 carbons in the ringstructure.

Throughout the description, where compositions and kits are described ashaving, including, or comprising specific components, or where processesand methods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions andkits of the present invention that consist essentially of, or consistof, the recited components, and that there are processes and methodsaccording to the present invention that consist essentially of, orconsist of, the recited processing steps.

As a general matter, compositions specifying a percentage are by weightunless otherwise specified. Further, if a variable is not accompanied bya definition, then the previous definition of the variable controls.

I. Therapeutic Methods

The invention provides methods for improving visual performance,reducing pupil diameter, and reducing an aberrant focus of scatteredlight rays in a patient's eye. The methods involve daily ophthalmicadministration of a phentolamine solution to an eye of a patient at ornear the bedtime of the patient. The daily ophthalmic administration ofa phentolamine solution is repeated for an extended duration, such asfor at least about five or seven consecutive days. Various aspects andembodiments of the therapeutic methods are described in the sectionsbelow. The sections are arranged for convenience and information in onesection is not to be limited to that section, but may be applied tomethods in other sections.

A. Methods for Improving Visual Performance

One aspect of the invention provides a method of improving visualperformance in a patient while minimizing eye redness during thepatient's waking hours. The method comprises administering to an eye ofa patient once per day at or near the bedtime of the patient for atleast five consecutive days a daily dosage of phentolamine or apharmaceutically acceptable salt thereof sufficient to provide improvedvisual performance for at least twenty hours, wherein the patientexperiences an increase in eye redness of no more than two gradesmeasured using the CCLRU Redness Grading Scale during the patient'swaking hours compared to the patient's level of eye redness withoutreceiving said dosage.

Visual performance pertains to the patient's overall vision quality andincludes a patient's ability to see clearly, as well as ability todistinguish between an object and its background. One aspect of visualperformance is visual acuity. Visual acuity is a measure of a patient'sability to see clearly. Visual acuity can be measured using, forexample, a Snellen chart. Further, the visual acuity measurement can betaken under scotopic conditions, mesopic conditions, and/or photopicconditions. Another aspect of visual performance is contrastsensitivity. Contrast sensitivity is a measure of the patient's abilityto distinguish between an object and its background. Contrastsensitivity can be measured using, for example, a Holladay AutomatedContrast Sensitivity System. The contrast sensitivity can be measuredunder various light conditions, including, for example, photopicconditions, mesopic conditions, and scotopic conditions, each eitherwith or without glare. In certain embodiments, the contrast sensitivityis measured under mesopic conditions either with or without glare.

In certain embodiments, the improvement in visual performance providedby the method is improved visual acuity. In certain embodiments, theimprovement in visual performance provided by the method is improvedvisual acuity under scotopic conditions. In certain embodiments, theimprovement in visual performance provided by the method is improvedvisual acuity under mesopic conditions. In certain embodiments, theimprovement in visual performance provided by the method is improvedvisual acuity under photopic conditions. In certain embodiments, theimprovement in visual acuity is a two-line improvement in the patient'svision as measured using the Snellen chart. In certain otherembodiments, the improvement in visual acuity is a one-line improvementin the patient's vision as measured using the Snellen chart.

In certain embodiments, the improvement in visual performance providedby the method is improved contrast sensitivity. The improvement incontrast sensitivity can be measured under various light conditions,such as photopic conditions, mesopic conditions, and scotopicconditions. In certain embodiments, the improvement in visualperformance provided by the method is improved contrast sensitivityunder photopic conditions. In certain embodiments, the improvement invisual performance provided by the method is improved contrastsensitivity under mesopic conditions. In certain embodiments, theimprovement in visual performance provided by the method is improvedcontrast sensitivity under scotopic conditions. Further, contrastsensitivity can be measured in the presence of glare or the absence ofglare. All combinations of light conditions and glare are contemplated.

Results achieved by the therapeutic methods can be characterizedaccording to the patient's improvement in contrast sensitivity. Forexample, in certain embodiments, the improvement in contrast sensitivityis at least a 10% (or 20%, 30%, 50%, 60%, or 70%) improvement measuredunder mesopic conditions using the Holladay Automated ContrastSensitivity System. In certain embodiments, the improvement in contrastsensitivity is at least a 10% (or 20%, 30%, 50%, 60%, or 70%)improvement measured under photopic conditions using the HolladayAutomated Contrast Sensitivity System. In certain other embodiments, theimprovement in contrast sensitivity is at least a 10% (or 20%, 30%, 50%,60%, or 70%) improvement measured under mesopic conditions or scotopicconditions using the Holladay Automated Contrast Sensitivity System.

In certain other embodiments, the improvement in visual performanceprovided by the method is both (i) improved visual acuity (such as underscotopic conditions, mesopic conditions, and/or photopic conditions) and(ii) improved contrast sensitivity (such as under scotopic conditions,mesopic conditions, and/or photopic conditions).

The degree of eye redness can be evaluated and characterized usingprocedures described in the literature, such as the Cornea and ContactLens Research Unit (CCLRU) Redness Grading Scale developed by the Schoolof Optometry, University of New South Wales. See, for example, Terry etal. in Optom. Vis. Sci. (1993) vol. 70, pages 234-243; and Pult et al.in Ophthal. Physiol. Opt. (2008) vol. 28, pages 13-20. The CCLRU RednessGrading Scale evaluates eye redness on a four-point scale: (0) no eyeredness, (1) very slight eye redness, (2) slight eye redness, (3)moderate eye redness, and (4) severe eye redness. See FIG. 11 for anillustration of the eye redness scale.

In certain embodiments, the patient experiences an increase in eyeredness of no more than one grade measured using the CCLRU RednessGrading Scale during the patient's waking hours compared to thepatient's level of eye redness without receiving said dosage.

The daily dosage of phentolamine or a pharmaceutically acceptable saltthereof can be administered for greater than five consecutive days. Forexample, in certain embodiments, the daily dosage of phentolamine or apharmaceutically acceptable salt thereof is administered for at leastseven consecutive days. In yet other embodiments, the daily dosage ofphentolamine or a pharmaceutically acceptable salt thereof isadministered for at least 10, 15, 20, 30, 60, 90, or 120 consecutivedays, or even a larger number of consecutive days. One benefit of theinvention is that the phentolamine or a pharmaceutically acceptable saltthereof can be used on a chronic basis, that is the dosage can beadministered daily for a large number of consecutive days. Eye rednessassociated with administration of phentolamine or a pharmaceuticallyacceptable salt thereof did not worsen with consecutive dailyadministration of phentolamine or a pharmaceutically acceptable salt,and no diminution in efficacy of the phentolamine solution was observedafter daily administration for an extended period of time. Exemplarydurations of chronic use include, for example, daily use over a periodof about 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or longer.

The amount of phentolamine or a pharmaceutically acceptable salt thereofin the daily dosage is sufficient to provide improved visual performancefor at least twenty hours. In certain embodiments, the amount ofphentolamine or a pharmaceutically acceptable salt thereof in the dailydosage is sufficient to provide improved visual performance for at leasttwenty-four hours. In yet other embodiments, the amount of phentolamineor a pharmaceutically acceptable salt thereof in the daily dosage issufficient to provide improved visual performance for at leastthirty-six hours, forty-eight hours, sixty hours, or seventy-two hours.In still other embodiments, the amount of phentolamine or apharmaceutically acceptable salt thereof in the daily dosage issufficient to provide improved visual performance for at least 4, 5, 6,7, 8, 9, 10, or 11 days. In certain embodiments, the daily dosage isabout one eye drop per eye of an ophthalmic solution comprising fromabout 0.1% (w/v) to about 2.0% (w/v) phentolamine mesylate. In certainother embodiments, the daily dosage is about one eye drop per eye of anophthalmic solution comprising from about 0.25% (w/v) to about 1.0%(w/v) phentolamine mesylate, or from about 0.5% (w/v) to about 1.0%(w/v) phentolamine mesylate.

B. Methods for Reducing Pupil Diameter

Another aspect of the invention provides methods for reducing pupildiameter in a patient while minimizing eye redness during the patient'swaking hours. The method comprises administering to an eye of a patientonce per day at or near the bedtime of the patient for at least fiveconsecutive days a daily dosage of phentolamine or a pharmaceuticallyacceptable salt thereof sufficient to reduce pupil diameter for at leasttwenty hours, wherein the patient experiences an increase in eye rednessof no more than two grades measured using the CCLRU Redness GradingScale during the patient's waking hours compared to the patient's levelof eye redness without receiving said dosage. The reduction in pupildiameter is understood to provide improvements in visual performance forthe patient.

The reduction in pupil diameter can be characterized according to, forexample, the percent reduction in pupil diameter and size of the pupilmeasured under certain light conditions. Accordingly, in certainembodiments, the reduction in pupil diameter under mesopic conditions isat least 5% compared to the pupil diameter of the patient under the samemesopic conditions but not having received the aqueous ophthalmicsolution. In certain other embodiments, the reduction in pupil diameterunder mesopic conditions is at least 10% compared to the pupil diameterof the patient under the same mesopic conditions but not having receivedthe aqueous ophthalmic solution. In certain other embodiments, thepatient experiences a reduction in pupil diameter of at least 0.5 mmwhen measured under mesopic conditions relative to the diameter of thepatient's pupil under the same mesopic conditions but not havingreceived the aqueous ophthalmic solution. In certain other embodiments,the patient experiences a reduction in pupil diameter ranging from about0.6 mm to about 3 mm, about 0.6 mm to about 2.5 mm, or about 0.6 mm toabout 2 mm when measured under mesopic conditions relative to thediameter of the patient's pupil under the same mesopic conditions butnot having received the aqueous ophthalmic solution. In certain otherembodiments, the patient experiences a reduction in pupil diameterranging from about 0.6 mm to about 1.2 mm when measured under mesopicconditions relative to the diameter of the patient's pupil under thesame mesopic conditions but not having received the aqueous ophthalmicsolution. In yet other embodiments, the patient's pupil is reduced to adiameter of about 3 mm to about 5 mm, about 3 mm to about 6 mm, about 4mm to about 5 mm, about 4 mm to about 6 mm, or about 4 mm to about 7 mmunder mesopic conditions due to the aqueous ophthalmic solution. Incertain embodiments, the patient's pupil is reduced to a diameter ofabout 4 mm to about 6 mm under mesopic conditions due to the aqueousophthalmic solution.

In certain other embodiments, the reduction in pupil diameter underscotopic conditions is at least 5% compared to the pupil diameter of thepatient under the same scotopic conditions but not having received theaqueous ophthalmic solution. In certain other embodiments, the reductionin pupil diameter under scotopic conditions is at least 10% compared tothe pupil diameter of the patient under the same scotopic conditions butnot having received the aqueous ophthalmic solution. In certain otherembodiments, the patient experiences a reduction in pupil diameter of atleast 0.5 mm when measured under scotopic conditions relative to thediameter of the patient's pupil under the same scotopic conditions butnot having received the aqueous ophthalmic solution. In certain otherembodiments, the patient experiences a reduction in pupil diameterranging from about 0.6 mm to about 3 mm, about 0.6 mm to about 2.5 mm,or about 0.6 mm to about 2 mm when measured under scotopic conditionsrelative to the diameter of the patient's pupil under the same scotopicconditions but not having received the aqueous ophthalmic solution. Incertain other embodiments, the patient experiences a reduction in pupildiameter ranging from about 0.6 mm to about 1.2 mm when measured underscotopic conditions relative to the diameter of the patient's pupilunder the same scotopic conditions but not having received the aqueousophthalmic solution. In yet other embodiments, the patient's pupil isreduced to a diameter of about 3 mm to about 5 mm, about 3 mm to about 6mm, about 4 mm to about 5 mm, about 4 mm to about 6 mm, or about 4 mm toabout 7 mm under scotopic conditions due to the aqueous ophthalmicsolution. In certain embodiments, the patient's pupil is reduced to adiameter of about 4 mm to about 6 mm under scotopic conditions due tothe aqueous ophthalmic solution.

The daily dosage of phentolamine or a pharmaceutically acceptable saltthereof can be administered for greater than five consecutive days. Forexample, in certain embodiments, the daily dosage of phentolamine or apharmaceutically acceptable salt thereof is administered for at leastseven consecutive days. In yet other embodiments, the daily dosage ofphentolamine or a pharmaceutically acceptable salt thereof isadministered for at least 10, 15, or 20 consecutive days or longer. Onebenefit of the invention is that the phentolamine or a pharmaceuticallyacceptable salt thereof can be used on a chronic basis, that is thedosage can be administered daily for a large number of consecutive days.Eye redness associated with administration of phentolamine or apharmaceutically acceptable salt thereof did not worsen with consecutivedaily administration of phentolamine or a pharmaceutically acceptablesalt, and no diminution in efficacy of the phentolamine solution wasobserved after daily administration for an extended period of time.Exemplary durations of chronic use include, for example, daily use overa period of about 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or longer.

The amount of phentolamine or a pharmaceutically acceptable salt thereofin the daily dosage is sufficient to reduce pupil diameter for at leasttwenty hours. In certain embodiments, the amount of phentolamine or apharmaceutically acceptable salt thereof in the daily dosage issufficient to reduce pupil diameter for at least twenty-four hours. Inyet other embodiments, the amount of phentolamine or a pharmaceuticallyacceptable salt thereof in the daily dosage is sufficient to reducepupil diameter for at least thirty-six hours, forty-eight hours, sixtyhours, or seventy-two hours. In still other embodiments, the amount ofphentolamine or a pharmaceutically acceptable salt thereof in the dailydosage is sufficient to reduce pupil diameter for at least 4, 5, 6, 7,8, 9, 10, or 11 days. In certain embodiments, the daily dosage is aboutone eye drop per eye of an ophthalmic solution comprising from about0.5% (w/v) to about 1.0% (w/v) phentolamine mesylate. In certain otherembodiments, the daily dosage is about one eye drop per eye of anophthalmic solution comprising from about 0.25% (w/v) to about 1.0%(w/v) phentolamine mesylate.

In certain embodiments, the patient experiences an increase in eyeredness of no more than one grade measured using the CCLRU RednessGrading Scale during the patient's waking hours compared to thepatient's level of eye redness without receiving said dosage.

C. Methods for Reducing Aberrant Focus of Scattered Light Rays in aPatient's Eye

Another benefit of the therapies described herein is that they canimprove visual performance in a patient by reducing the aberrant focusof scattered light rays in the patient's eye. Accordingly, one aspect ofthe invention provides a method of reducing an aberrant focus ofscattered light rays in a patient's eye while minimizing eye rednessduring the patient's waking hours. The method comprises administering toan eye of a patient once per day at or near the bedtime of the patientfor at least five consecutive days a daily dosage of phentolamine or apharmaceutically acceptable salt thereof sufficient to reduce aberrantfocus of scattered light rays in a patient's eye for at least twentyhours, wherein the patient experiences an increase in eye redness of nomore than two grades measured using the CCLRU Redness Grading Scaleduring the patient's waking hours compared to the patient's level of eyeredness without receiving said dosage.

In certain embodiments, the patient experiences an increase in eyeredness of no more than one grade measured using the CCLRU RednessGrading Scale during the patient's waking hours compared to thepatient's level of eye redness without receiving said dosage.

The daily dosage of phentolamine or a pharmaceutically acceptable saltthereof can be administered for greater than five consecutive days. Forexample, in certain embodiments, the daily dosage of phentolamine or apharmaceutically acceptable salt thereof is administered for at leastseven consecutive days. In yet other embodiments, the daily dosage ofphentolamine or a pharmaceutically acceptable salt thereof isadministered for at least 10, 15, or 20 consecutive days or longer. Onebenefit of the invention is that the phentolamine or a pharmaceuticallyacceptable salt thereof can be used on a chronic basis, that is thedosage can be administered daily for a large number of consecutive days.Eye redness associated with administration of phentolamine or apharmaceutically acceptable salt thereof did not worsen with consecutivedaily administration of phentolamine or a pharmaceutically acceptablesalt, and no diminution in efficacy of the phentolamine solution wasobserved after daily administration for an extended period of time.Exemplary durations of chronic use include, for example, daily use overa period of about 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or longer.

The amount of phentolamine or a pharmaceutically acceptable salt thereofin the daily dosage is sufficient to reduce aberrant focus of scatteredlight rays in a patient's eye for at least twenty hours. In certainembodiments, the amount of phentolamine or a pharmaceutically acceptablesalt thereof in the daily dosage is sufficient reduce aberrant focus ofscattered light rays in a patient's eye for at least twenty-four hours.In yet other embodiments, the amount of phentolamine or apharmaceutically acceptable salt thereof in the daily dosage issufficient to reduce aberrant focus of scattered light rays in apatient's eye for at least thirty-six hours, forty-eight hours, sixtyhours, or seventy-two hours. In certain embodiments, the daily dosage isabout one eye drop per eye of an ophthalmic solution comprising fromabout 0.5% (w/v) to about 1.0% (w/v) phentolamine mesylate. In certainother embodiments, the daily dosage is about one eye drop per eye of anophthalmic solution comprising from about 0.25% (w/v) to about 1.0%(w/v) phentolamine mesylate.

D. General Considerations for Therapeutic Methods

General considerations that may be applied to therapeutic methodsdescribed herein (e.g., the methods described in Parts A-C above) areprovided below and include, for example, the form of the daily dosage,time of day when the daily dosage is administered, additional proceduresfor evaluating improvement in visual performance, and patientpopulations that may derive particular benefits from the therapeuticmethods.

The daily dosage of phentolamine or a pharmaceutically acceptable saltthereof is desirably administered to the eye of the patient in the formof an ophthalmic solution, which is delivered to the eye in the form ofeye drop. A standard eye drop typically contains from about 0.03 mL toabout 0.05 mL of solution.

Various methods described above require administration of the dailydosage at or near the bedtime of the patient. Accordingly, in certainembodiments, the daily dosage is administered within 2 hours, 1.5 hours,1 hour, 45 minutes, 30 minutes, or 15 minutes of patient's bedtime. Incertain embodiments, the daily dosage is administered within 1 hour ofthe patient's bedtime.

The methods can be further characterized according to improvement invisual acuity measured using a Snellen chart. For example, in certainembodiments, the method results in an improvement in visual acuitycharacterized by at least a one-line improvement in the patient's visionmeasured using a Snellen chart. In certain other embodiments, the methodresults in an improvement in visual acuity characterized by at least atwo-line improvement in the patient's vision measured using a Snellenchart. The improvement in visual acuity can be measured under photopicconditions, mesopic conditions, and/or scotopic conditions. Further, thevisual acuity measurement can be taken under conditions that testlow-contrast visual acuity or under conditions that test high-contrastvisual acuity.

Certain patient populations may respond particularly well to thetherapeutic methods. One way to characterize patients is according toeye color, such as those having a substantial amount of pigment in theiriris. As such, one population of patients is those in which thepatient's iris is brown. Another way to characterize patient populationsis according to race, such as African American, Hispanic, and Asianpatients.

It is reiterated here that all embodiments described throughout thepatent application (including, for example, Sections A-C) may becombined in various permutations and all such permutations arecontemplated. For example, it is contemplated that the method ofproviding improvement in visual performance in a patient described inSection A may be further characterized according to, for example, (i)changes in pupil diameter described in Section C and/or (ii)administering the ophthalmic solution within one hour of the patient'sbedtime as described in Section D. Likewise, the methods in Sections B-Dcan be characterized according to embodiments described in Section A,such as those pertaining to threshold improvements in visualperformance, such as where (i) the method results in at least at least a10% (or 20%, 30%, 50%, 60%, or 70%) improvement in contrast sensitivitymeasured under mesopic conditions using the Holladay Automated ContrastSensitivity System.

II. Ophthalmic Solutions Containing Phentolamine

The therapeutic methods involve administering a daily dosage ofphentolamine or a pharmaceutically acceptable salt thereof to thepatient. The daily dosage of phentolamine or a pharmaceuticallyacceptable salt thereof is desirably in the form of an ophthalmicsolution. The ophthalmic solution is formulated to be suitable foradministration to the eye of a patient, and desirably provides immediaterelease of phentolamine, that is, the ophthalmic solution is not asustained release formulation that delivers phentolamine over anextended duration, such as hours, days or weeks.

The ophthalmic solution desirably comprises an aqueous pharmaceuticallyacceptable carrier and phentolamine or a pharmaceutically acceptablesalt thereof. The ophthalmic solution may contain excipients(s) that aresuitable for administration to the eye. Various pharmaceuticallyacceptable salts are described in the literature. The preferred saltform of phentolamine is phentolamine mesylate. Accordingly, the methodsmay use an ophthalmic solution that comprises an aqueouspharmaceutically acceptable carrier and phentolamine mesylate.

Accordingly, in certain embodiments, the daily dosage utilized in themethods is an ophthalmic solution comprising an aqueous pharmaceuticallyacceptable carrier and phentolamine or a pharmaceutically acceptablesalt thereof. In certain other embodiments, the daily dosage is anophthalmic solution comprising an aqueous pharmaceutically acceptablecarrier and phentolamine mesylate. In certain other embodiments, thedaily dosage is an ophthalmic solution comprising water, a polyol, andphentolamine or a pharmaceutically acceptable salt thereof. In certainother embodiments, the daily dosage is an ophthalmic solution comprisingwater, mannitol, and phentolamine mesylate. In certain otherembodiments, the daily dosage is an ophthalmic solution comprisingwater, a polyol, an alkali metal carboxylate, and phentolamine or apharmaceutically acceptable salt thereof. In certain other embodiments,the daily dosage is an ophthalmic solution comprising water, mannitol,sodium acetate, and phentolamine mesylate.

Other ophthalmic solutions that are contemplated for use in the presentinvention include, for example, (i) aqueous ophthalmic solutions free ofa chelating agent, and (ii) polyvinylpyrrolidone artificial tearsformulations, each of which are described in more detail below.

Aqueous Ophthalmic Solution Free of a Chelating Agent

In certain embodiments, the daily dosage utilized in the methods is anaqueous ophthalmic solution free of a chelating agent, wherein saidsolution comprises (a) phentolamine or a pharmaceutically acceptablesalt thereof; (b) at least one polyol compound, such as a polyolcompound having a molecular weight less than 250 g/mol; (c) at least onebuffer; and (d) water; wherein the solution does not contain a chelatingagent. The amount of ingredients in the aqueous ophthalmic solutions maybe selected in order to achieve particular performance properties, suchas stability to storage, minimize irritation to the eye of a patient,and enhance penetration of phentolamine into the eye of a patient.

One exemplary preferred solution is an aqueous ophthalmic solution freeof a chelating agent comprising: (a) about 0.1% (w/v) to about 4% (w/v)of phentolamine or a pharmaceutically acceptable salt thereof; (b) about1% (w/v) to about 6% (w/v) of at least one polyol compound having amolecular weight less than 250 g/mol; (c) about 0.1 mM to about 10 mM ofat least one buffer; and (d) water; wherein the solution has a pH in therange of 4.0 to 7.5 and does not contain a chelating agent.

Exemplary components and features of the aqueous ophthalmic solutionsare described in more detail below.

Phentolamine & Pharmaceutically Acceptable Salts

The aqueous ophthalmic solution comprises phentolamine or apharmaceutically acceptable salt of phentolamine. Exemplarypharmaceutically acceptable salts include, for example, the hydrochloricacid salt and mesylate salt. Accordingly, in certain embodiments, thesolution comprises phentolamine (i.e., as the free base). In certainother embodiments, the solution comprises phentolamine hydrochloride. Incertain yet other embodiments, the solution comprises phentolaminemesylate.

The amount of phentolamine or a pharmaceutically acceptable salt thereofin the aqueous ophthalmic solution may be adjusted in order to achievedesired performance properties. For example, where is it desired toprovide a larger amount of phentolamine (or pharmaceutically acceptablesalt thereof) to the patient in a single administration of the aqueousophthalmic solution, the concentration of phentolamine (orpharmaceutically acceptable salt thereof) is increased in the aqueousophthalmic solution. Single administration of aqueous ophthalmicsolutions having a higher concentration of phentolamine (orpharmaceutically acceptable salt thereof) may provide the patient withimproved visual performance for a longer duration of time because morephentolamine (or pharmaceutically acceptable salt thereof) isadministered to the patient.

Accordingly, in certain embodiments, the aqueous ophthalmic solutioncomprises from about 0.1% (w/v) to about 2% (w/v) of phentolamine or apharmaceutically acceptable salt thereof. In certain embodiments, theaqueous ophthalmic solution comprises from about 0.25% (w/v) to about 2%(w/v) of phentolamine or a pharmaceutically acceptable salt thereof. Incertain other embodiments, the aqueous ophthalmic solution comprisesfrom about 0.5% (w/v) to about 2% (w/v) of phentolamine or apharmaceutically acceptable salt thereof. In certain other embodiments,the aqueous ophthalmic solution comprises from about 0.25% (w/v) toabout 1% (w/v) of phentolamine or a pharmaceutically acceptable saltthereof. In certain other embodiments, the aqueous ophthalmic solutioncomprises about 1% (w/v) of phentolamine or a pharmaceuticallyacceptable salt thereof. In certain other embodiments, the aqueousophthalmic solution comprises from about 0.1% (w/v) to about 4% (w/v) ofphentolamine mesylate. In certain other embodiments, the aqueousophthalmic solution comprises from about 0.1% (w/v) to about 2% (w/v) ofphentolamine mesylate. In certain other embodiments, the aqueousophthalmic solution comprises from about 0.25% (w/v) to about 2% (w/v)of phentolamine mesylate. In certain other embodiments, the aqueousophthalmic solution comprises from about 0.5% (w/v) to about 2% (w/v) ofphentolamine mesylate. In certain other embodiments, the aqueousophthalmic solution comprises from about 0.25% (w/v) to about 1% (w/v)of phentolamine mesylate. In certain other embodiments, the aqueousophthalmic solution comprises about 1% (w/v) of phentolamine mesylate.In certain other embodiments, the aqueous ophthalmic solution comprisesabout 0.25% (w/v) or about 0.5% (w/v) of phentolamine mesylate.

Polyol Compounds

The aqueous ophthalmic solution comprises one or more polyol compounds.The polyol compound is an organic compound having at least two hydroxylgroups (e.g., from 2 to about 6 hydroxyl groups). The polyol compound isbeneficial to the aqueous ophthalmic solution because, for example, itcan increase the stability of the aqueous ophthalmic solution to storageand/or modify the tonicity of the aqueous ophthalmic solution. Exemplarypolyol compounds include, for example, mannitol, glycerol, propyleneglycol, ethylene glycol, sorbitol, and xylitol.

The aqueous ophthalmic solution may contain a single polyol compound ora mixture of one or more polyol compounds. In other words, the aqueousophthalmic solution comprises at least one polyol compound. In certainembodiments, the aqueous ophthalmic solution comprises at least onepolyol compound that is mannitol, glycerol, propylene glycol, ethyleneglycol, sorbitol, or xylitol. In certain other embodiments, the at leastone polyol compound is mannitol. In certain other embodiments, the atleast one polyol compound is glycerol. In certain other embodiments, theat least one polyol compound is propylene glycol. In certain otherembodiments, the at least one polyol compound is mannitol, and thesolution further comprises glycerol. In certain other embodiments, theat least one polyol compound is mannitol, and the solution furthercomprises propylene glycol. In certain other embodiments, the at leastone polyol compound is glycerol, and the solution further comprisespropylene glycol. In certain other embodiments, the mannitol describedin embodiments above is D-mannitol.

The amount of the at least one polyol compound in the aqueous ophthalmicsolution may be selected in order to achieve desired performanceproperties for the solution. The polyol compound may, for example,increase the stability of the solution to storage and/or modify thetonicity of the solution to make it more suitable for administration tothe eye of a patient. In certain embodiments, the aqueous ophthalmicsolution comprises from about 2% (w/v) to about 5% (w/v) of the at leastone polyol compound. In certain other embodiments, the aqueousophthalmic solution comprises from about 3.5% (w/v) to about 4.5% (w/v)of the at least one polyol compound. In certain other embodiments, theaqueous ophthalmic solution comprises about 4% (w/v) of the at least onepolyol compound. In certain other embodiments, the aqueous ophthalmicsolution comprises from about 2%. (w/v) to about 3% (w/v) mannitol, andabout 0.5% (w/v) to about 1.5% (w/v) glycerin. In certain otherembodiments, the mannitol described in embodiments above is D-mannitol.

In certain embodiments, the amount of polyol may be selected based onthe amount of phentolamine (or pharmaceutically acceptable saltthereof), such that there is an inverse relationship between the amountof phentolamine (or pharmaceutically acceptable salt thereof) and thepolyol in order to achieve isotonicity with the eye. For example, inembodiments where the aqueous ophthalmic solution contains about 2%(w/v) phentolamine, mannitol is present in the solution at aconcentration of about 3% (w/v). In embodiments where the aqueousophthalmic solution contains about 1% (w/v) phentolamine, mannitol ispresent in the solution at a concentration of about 4% (w/v). To furtherillustrate this principle, in embodiments where the aqueous ophthalmicsolution contains about 0.5% (w/v) phentolamine, mannitol may be presentin the solution at a concentration of about 4.5% (w/v). In certainembodiments, the mannitol described in embodiments above is D-mannitol.

It is appreciated that the aqueous ophthalmic solution can containadditional ingredients described herein, such as various polymermaterials. One such embodiment is an aqueous ophthalmic solutioncomprising, for example, at least one polyol compound that is propyleneglycol, and further comprising polypropylene glycol, such aspolypropylene glycol having a weight average molecular weight in therange of about 5,000 g/mol to about 100,000 g/mol.

Poly(C₂₋₄Alkylene)Glycol Polymer

The aqueous ophthalmic solution may optionally comprise a poly(C₂₋₄alkylene)glycol polymer. An exemplary poly(C₂₋₄alkylene)glycol polymeris polypropylene glycol, such as a polypropylene glycol having a weightaverage molecular weight in the range of about 5,000 g/mol to about100,000 g/mol, about 10,000 g/mol to about 50,000 g/mol, or about 50,000g/mol to about 100,000 g/mol.

Dextran

The aqueous ophthalmic solution may optionally comprise dextran. Dextranis a commercially available, branched polysaccharide comprising glucosemolecules. The amount of dextran in the aqueous ophthalmic solution maybe selected to achieve certain performance properties. In certainembodiments, the aqueous ophthalmic solution comprises from about 0.01%(w/v) to about 2% (w/v) dextran. In certain other embodiments, theaqueous ophthalmic solution comprises from about 0.01% (w/v) to about 1%(w/v) dextran.

The dextran may be further characterized according to its weight averagemolecular weight. In certain embodiments, the dextran has a weightaverage molecular weight in the range of about 65,000 g/mol to about75,000 g/mol. In certain other embodiments, the dextran has a weightaverage molecular weight of about 70,000 g/mol. In yet otherembodiments, the dextran has a weight average molecular weight in therange of about 5,000 g/mol to about 100,000 g/mol, about 10,000 g/mol toabout 50,000 g/mol, or about 50,000 g/mol to about 100,000 g/mol.

Cellulose Agent

The aqueous ophthalmic solution may optionally comprise a celluloseagent. Exemplary cellulose agents include, for example, cellulose,carboxymethyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose,and hydroxypropylmethyl cellulose. In certain embodiments, the celluloseagent is hydroxypropylmethyl cellulose. In certain other embodiments,the cellulose agent is cellulose, carboxymethyl cellulose,hydroxyethylcellulose, or hydroxypropylcellulose. The amount ofcellulose agent in the aqueous ophthalmic solution may be selected inorder to achieve desired performance properties. For example, in certainembodiments, the aqueous ophthalmic solution comprises from about 0.01%(w/v) to about 2% (w/v) cellulose agent.

The cellulose agent may be further characterized according to its weightaverage molecular weight. In certain embodiments, the cellulose agenthas a weight average molecular weight in the range of about 5,000 g/molto about 100,000 g/mol, about 10,000 g/mol to about 50,000 g/mol, orabout 50,000 g/mol to about 100,000 g/mol.

Buffer

The aqueous ophthalmic solution comprises at least one buffer. Thebuffer imparts to the solution a buffering capacity, that is, thecapacity to neutralize, within limits, either acids or bases (alkali)with relatively little or no change in the original pH. The buffer maybe an acid, a base, or a combination of an acid and a base. The buffermay be organic, inorganic, or a combination of organic and inorganiccomponents. It should be understood that the buffer at least partiallydissociates in aqueous solution to form a mixture of, e.g., an acid andconjugate base or a base and conjugate acid. For example, the buffer maybe a combination of a carboxylic acid and its carboxylate salt. Inanother embodiment, the buffer may be a combination of an acid and abase, where the acid and the base are not conjugates. For example, theacid may be boric acid and the base may betris(hydroxymethyl)aminomethane (TRIS).

Exemplary buffers include organic acids (e.g., acetic acid, sorbic acid,and oxalic acid), a borate salt, a hydrogen carbonate salt, a carbonatesalt, a gluconate salt, a lactate salt, a phosphate salt, a propionatesalt, a perborate salt, tris-(hydroxymethyl)aminomethane (TRIS),bis(2-hydroxyethyl)-imino-tris-(hydroxymethyl)aminoalcohol (bis-tris),N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine (tricene),N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine,3-(N-morpholino)propanesulfonic acid, N-(carbamoylmethyl)taurine (ACES),an amino acid, salts thereof, and combinations thereof. It should beunderstood that the salt form of a buffer may comprise any suitablecounterion. For example, the salt form of an acid may comprise an alkalior alkaline earth metal counterion.

The buffer can be characterized according to its strength, i.e., thebuffering capacity. The buffering capacity can be tested, for example,by determining the millimoles (mM) of strong acid or base (orrespectively, hydrogen or hydroxide ions) required to change the pH of abuffer solution by one unit when added to one liter (a standard unit) ofthe buffer solution. The buffering capacity generally depends on thetype and concentration of the buffer components and can be greater inparticular pH ranges. For example, a buffer may have an optimalbuffering capacity in a pH range near the pK_(a) of the buffer, e.g.,within about 1 pH unit or within about 2 pH units of the pK_(a) thebuffer. In certain embodiments, the buffer is a weak buffer, such as analkali metal carboxylate (e.g., sodium acetate).

In certain embodiments, the buffer is a weak acid buffer having one ormore of the following characteristics: (a) a pKa of from about 4.0 toabout 6.0; more preferably, from about 4.5 to about 5.5; and (b) alipophilicity value Log P of from about −0.50 to about 1.5; morepreferably, from about −0.25 to about 1.35.

The amount of buffer can be adjusted in order to achieve desiredperformance properties for the aqueous ophthalmic solution. For example,in certain embodiments, the buffer may be present at a concentration ofless than about 10 mM, less than about 7 mM, less than about 5 mM, lessthan about 3 mM, or less than about 2 mM. In some embodiments, thebuffer may be present at a concentration of from about 1 mM to about 10mM, from about 1 mM to about 7 mM, from about 1 mM to about 5 mM, fromabout 1 mM to about 3 mM, from about 1 mM to about 2 mM, from about 2 mMto about 5 mM, or from about 2 mM to about 3 mM. In yet otherembodiments, the buffer is present at a concentration of about 3 mM.

The amount and identity of the buffer may be selected in order toachieve certain performance properties for the aqueous ophthalmicsolution. For example, the amount of buffer may impact the quantity ofacid that may be neutralized before there is substantial change in thepH of the aqueous ophthalmic solution. Also, the amount of buffer mayimpact the tonicity of the aqueous ophthalmic solution. Desirably, thequantity and identity of the buffer should be selected in order tominimize any irritation that may be caused by administration of theaqueous ophthalmic solution to the eye of a patient. Accordingly, incertain embodiments, the buffer is present at a concentration in therange of about 2 mM to about 4 mM. In yet other embodiments, the bufferis present at a concentration of about 3 mM. In certain embodiments, thebuffer comprises an alkali metal alkylcarboxylate. In certain otherembodiments, the buffer comprises an alkali metal acetate. In yet otherembodiments, the buffer comprises sodium acetate.

Solution pH

The aqueous ophthalmic solution may be characterized according to the pHof the solution. Desirably, the aqueous ophthalmic solution has a pH inthe range of 4.0 to 7.5. In certain embodiments, the aqueous ophthalmicsolution has a pH in the range of 4.5 to 7.5. In certain embodiments,the solution has a pH in the range of 4.5 to 6.0. In certain otherembodiments, the solution has a pH in the range of 4.5 to 5.5. In yetother embodiments, the solution has a pH in the range of 4.7 to 5.1.

Additional Materials for Aqueous Ophthalmic Solutions

The aqueous ophthalmic solutions may contain additional materials inorder to make the composition more suitable for administration to theeye of a patient. Exemplary additional materials are described below andinclude, for example, a tonicity modifier, preservative, antioxidant,viscosity modifying agent, stabilizing agent, corneal permeationenhancing agent, and surfactants.

A. Tonicity Modifier

The aqueous ophthalmic solution may optionally comprise one or moretonicity modifiers. The tonicity modifier may be ionic or non-ionic. Incertain embodiments, the tonicity modifier may be a salt, acarbohydrate, or a polyol. Exemplary tonicity modifiers include alkalimetal or alkaline earth metal halides (such as LiBr, LiCl, LiI, KBr,KCl, KI, NaBr, NaCl, NaI, CaCl₂, and MgCl₂), boric acid, dextran (e.g.,Dextran 70), cyclodextrin, dextrose, mannitol, glycerin, urea, sorbitol,propylene glycol, or a combination thereof.

It is appreciated that the tonicity modifier may be added to the aqueousophthalmic solution in an amount sufficient to provide a desiredosmolality. In certain embodiments, the tonicity modifier is present inthe aqueous ophthalmic solution in an amount sufficient so that theaqueous ophthalmic solution has an osmolality ranging from about 50 toabout 1000 mOsm/kg, from about 100 to about 400 mOsm/kg, from about 200to about 400 mOsm/kg, or from about 280 to about 380 mOsm/kg. In certainembodiments, a tonicity modifier may be present in an amount rangingfrom about 0.01% (w/v) to about 7% (w/v), about 0.01% (w/v) to about 5%(w/v), about 0.01% (w/v) to about 1% (w/v), about 0.1% (w/v) to about 1%(w/v), about 0.05% (w/v) to about 5% (w/v), about 0.05% (w/v) to about0.5% (w/v), about 1% (w/v) to about 3% (w/v), or about 2% (w/v) to about4% (w/v), of the aqueous ophthalmic solution.

B. Preservative

The aqueous ophthalmic solution may optionally comprise one or morepreservatives in order to, for example, reduce or prevent microbialcontamination. Exemplary preservatives include quaternary ammonium saltssuch as polyquarternium-1, cetrimide, benzalkonium chloride, orbenzoxonium chloride; alkyl-mercury salts of thiosalicylic acid such asthiomersal, phenylmercuric nitrate, phenylmercuric acetate, orphenylmercuric borate; parabens such as methylparaben or propylparaben;alcohols such as chlorobutanol, benzyl alcohol, phenyl ethanol,cyclohexanol, 3-pentanol, or resorcinol; a peroxide; chlorine dioxide orPURITE; guanidine derivatives such as chlorohexidine gluconate orpolyaminopropyl biguanide; and combinations thereof.

The amount of preservative can be adjusted in order to achieve desiredperformance properties for the aqueous ophthalmic solution. In certainembodiments, the preservative is present in an amount less than about 5%(w/v), 3% (w/v), 1% (w/v), or 0.1% (w/v) of the aqueous ophthalmicsolution. In certain other embodiments, the preservative is present inan amount ranging from about 0.01% (w/v) to about 5% (w/v), about 0.01%(w/v) to about 1% (w/v), about 0.1% (w/v) to about 1% (w/v), about 0.05%(w/v) to about 5% (w/v), or about 0.05% (w/v) to about 0.5% (w/v), ofthe aqueous ophthalmic solution.

C. Antioxidant

The aqueous ophthalmic solution may optionally comprise one or moreantioxidants. Exemplary antioxidants for use in the aqueous ophthalmicsolutions described herein include water soluble antioxidants such asascorbic acid, cysteine hydrochloride, sodium bisulfate, sodiummetabisulfite, sodium bisulfite, sodium sulfite, and the like; andoil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like.

The amount of antioxidant can be adjusted in order to achieve desiredperformance properties for the aqueous ophthalmic solution. In certainembodiments, the antioxidant is present in an amount less than about 5%(w/v), 30% (w/v), 1% (w/v), or 0.1% (w/v) of the aqueous ophthalmicsolution. In certain other embodiments, the antioxidant is present in anamount ranging from about 0.01% (w/v) to about 5% (w/v), about 0.01%(w/v) to about 1% (w/v), about 0.1% (w/v) to about 1% (w/v), about 0.05%(w/v) to about 5% (w/v), or about 0.05% (w/v) to about 0.5% (w/v), ofthe aqueous ophthalmic solution.

D. Viscosity Modifying Agent

The aqueous ophthalmic solution may optionally comprise one or moreviscosity modifying agents. The viscosity modifying agent may be used,for example, to increase the absorption of an active agent or increasethe retention time of the aqueous ophthalmic solution in the eye.Exemplary viscosity modifying agents include polyvinylpyrrolidone,methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, carboxymethylcellulose (CMC) and salts thereof(e.g., CMC sodium salt), gelatin, cellulose glycolate, sorbitol,niacinamide, an alpha-cyclodextran, polyvinyl alcohol, polyethyleneglycol, hyaluronic acid, a polysaccharide, a monosaccharide, andcombinations thereof.

The amount of viscosity modifying agent can be adjusted in order toachieve desired performance properties for the aqueous ophthalmicsolution. In certain embodiments, the viscosity modifying agent ispresent in an amount less than about 10% (w/v), 5% (w/v), 3% (w/v), 1%(w/v), or 0.1% (w/v) of the aqueous ophthalmic solution. In certainother embodiments, the viscosity modifying agent is present in an amountranging from about 0.01% (w/v) to about 5% (w/v), about 0.01% (w/v) toabout 1% (w/v), about 0.1% (w/v) to about 1% (w/v), about 0.05% (w/v) toabout 5% (w/v), or about 0.05% (w/v) to about 0.5% (w/v), of the aqueousophthalmic solution. In certain other embodiments, the viscositymodifying agent is present in an amount sufficient to provide an aqueousophthalmic solution with a viscosity in the range of about 30 centipoiseto about 100 centipoise.

E. Corneal Permeation Enhancing Agent

The aqueous ophthalmic solution may optionally comprise one or moreagents for enhancing corneal permeation of phentolamine (or apharmaceutically acceptable salt thereof). Exemplary agents forenhancing corneal permeation include polymers, organic acids, esters ofan organic acid (e.g., a monoglyceride of fatty acid having 8 to 12carbon atoms), cyclodextrin, benzalkonium chloride (BAK), EDTA, caprylicacid, citric acid, boric acid, sorbic acid, polyoxyethylene-20-stearylether (PSE), polyethoxylated castor oil (PCO), deoxycholic acid sodiumsalt (DC), cetylpyridinium chloride (CPC), laurocapram,hexamethylenelauramide, hexamethyleneoctanamide, decylmethylsulfoxide,methyl sulfone, dimethyl sulfoxide, and combinations thereof.

The amount of corneal permeation enhancing agent can be adjusted inorder to achieve desired performance properties for the aqueousophthalmic solution. In certain embodiments, the corneal permeationenhancing agent is present in an amount less than about 10% (w/v), 5%(w/v), 1% (w/v), or 0.1% (w/v) of the aqueous ophthalmic solution. Incertain other embodiments, the corneal permeation enhancing agent ispresent in an amount ranging from about 0.01%/o (w/v) to about 5% (w/v),about 0.01% (w/v) to about 1% (w/v), about 0.1% (w/v) to about 1% (w/v),about 0.05% (w/v) to about 5% (w/v), about 0.05% (w/v) to about 0.5%(w/v), about 1% (w/v) to about 30% (w/v), or about 2% (w/v) to about 4%(w/v), of the aqueous ophthalmic solution.

F. Solubilizing Agent

The aqueous ophthalmic solution may optionally comprise one or moresolubilizing agents to improve the solubility of phentolamine (or apharmaceutically acceptable salt thereof) in the aqueous ophthalmicsolution. Exemplary solubilizing agents include, for example, a fattyacid glycerol poly-lower alkylene (i.e., a C₁ to C₇, linear or branched)glycol ester, fatty acid poly-lower alkylene glycol ester, polyalkyleneglycol (e.g., polyethylene glycol), glycerol ether of vitamin E,tocopherol polyethylene glycol 1000 succinate (TPGS), tyloxapol,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic F-68, F-84and P-103), cyclodextrin, and combinations thereof.

The amount of solubilizing agent can be adjusted in order to achievedesired performance properties for the aqueous ophthalmic solution. Incertain embodiments, the solubilizing agent is present in an amount lessthan about 10% (w/v), 5% (w/v), 3% (w/v), 1% (w/v), or 0.10% (w/v) ofthe aqueous ophthalmic solution. In certain other embodiments, thesolubilizing agent is present in an amount ranging from about 0.01%(w/v) to about 5% (w/v), about 0.01% (w/v) to about 1% (w/v), about 0.1%(w/v) to about 1% (w/v), about 0.05% (w/v) to about 5% (w/v), or about0.05% (w/v) to about 0.5% (w/v), of the aqueous ophthalmic solution.

G. Stabilizing Agent

The aqueous ophthalmic solution may optionally comprise one or morestabilizing agents in order to improve the stability of the aqueousophthalmic solution to storage, etc. Stabilizing agents described in thepharmaceutical literature are contemplated to be amenable for use in theaqueous ophthalmic solutions described herein. Exemplary stabilizingagents include an alcohol (e.g., polyols, such as mannitol, glycerol,propylene glycol, sorbitol, and xylitol), polyalkylene glycols such aspolyethylene glycol, polypropylene glycol, polyethylene glycol-nonphenolether, polyethylene glycol sorbitan monolaurate, polyethylene glycolsorbitan monooleate, polyethylene glycol sorbitan monooleate,polyethylene glycol stearate, polyethylene glycol polypropylene glycolether, polyvinyl alcohol, polyvinyl pyrrolidine, ascorbic acid, vitaminE, N-acetylcarnosine (NAC), sorbic acid, and combinations thereof. Incertain embodiments, the stabilizing agent is a polymer, such as one ofthe polymers mentioned above.

The amount of stabilizing agent can be adjusted in order to achievedesired performance properties for the aqueous ophthalmic solution. Incertain embodiments, the stabilizing agent is present in an amount lessthan about 10% (w/v), 5% (w/v), or 1% (w/v) of the aqueous ophthalmicsolution. In certain other embodiments, the stabilizing agent is presentin an amount ranging from about 0.01% (w/v) to about 5% (w/v), about0.01% (w/v) to about 1% (w/v), or about 0.01% (w/v) to about 0.1% (w/v)of the aqueous ophthalmic solution.

H. Surfactant

The aqueous ophthalmic solution may optionally comprise one or moresurfactants. Exemplary surfactants include Polysorbate 20 (i.e.,polyoxyethylene (20) sorbitan monolaurate), Polysorbate 40 (i.e.,polyoxyethylene (20) sorbitan monopalmitate), Polysorbate 60 (i.e.,polyoxyethylene (20) sorbitan monostearate), Polysorbate 80 (i.e.,polyoxyethylene (20) sorbitan monooleate), glyceryl stearate, isopropylstearate, polyoxyl stearate, propylene glycol stearate, sucrosestearate, polyethylene glycol, a polypropylene oxide, a polypropyleneoxide copolymer, Pluronic F68, Pluronic F-84, Pluronic P-103, an alcoholethoxylate, an alkylphenol ethoxylate, an alkyl glycoside, an alkylpolyglycoside, a fatty alcohol, hydroxypropylmethyl cellulose (HPMC),carboxymethyl cellulose (CMC), cyclodextrin, a polyacrylic acid,phosphatidyl choline, phosphatidyl serine, and combinations thereof.

The amount of surfactant can be adjusted in order to achieve desiredperformance properties for the aqueous ophthalmic solution. In certainembodiments, the surfactant is present in an amount less than about 10%(w/v), 5% (w/v), 3% (w/v), 1% (w/v), or 0.1% (w/v) of the aqueousophthalmic solution. In certain other embodiments, the surfactant ispresent in an amount ranging from about 0.01% (w/v) to about 5% (w/v),about 0.01% (w/v) to about 1% (w/v), about 0.1% (w/v) to about 1% (w/v),about 0.05% (w/v) to about 5% (w/v), or about 0.05% (w/v) to about 0.5%(w/v), of the aqueous ophthalmic solution.

I. Demulcent Polymers

The aqueous ophthalmic solution may optionally comprise one or moredemulcent polymers. Because of their ability to hold large amounts ofwater, demulcent polymers are useful for coating and moisturizing thecornea of the eye. Exemplary demulcent polymers include cellulosederivatives, dextran 40, dextran 70, gelatin, and liquid polyols.

J. Wetting Agents

The aqueous ophthalmic solution may optionally comprise one or morewetting agents. Wetting agents can be used to wet the surface of theeye. Exemplary wetting agents include polysorbates, poloxamers,tyloxapol, and lecithin.

K. Additional Materials

The aqueous ophthalmic solutions may optionally comprise one or moreadditional materials, such as acetylcysteine, cysteine, sodium hydrogensulfite, butyl-hydroxyanisole, butyl-hydroxytoluene, alpha-tocopherolacetate, thiourea, thiosorbitol, sodium dioctyl sulfosuccinate,monothioglycerol, lauric acid sorbitol ester, triethanol amine oleate,or palmitic acid esters.

Further, the aqueous ophthalmic solutions may comprise a carrier, suchas one or more of the exemplary carriers are described in for example,Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co.,Easton, Pa. [1975]). The carrier can be, for example, a mixture of waterand a water-miscible solvent (e.g., an alcohol such as glycerin, avegetable oil, or a mineral oil). Other exemplary carriers include amixture of water and one or more of the following materials:hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, analkali metal salt of carboxymethylcellulose, hydroxymethylcellulose,methylhydroxypropylcellulose, hydroxypropylcellulose, ethyl oleate,polyvinylpyrrolidone, an acrylate polymer, a methacrylate polymer, apolyacrylamide, gelatin, an alginate, a pectin, tragacanth, karaya gum,xanthan gum, carrageenin, agar, acacia, a starch (such as starch acetateor hydroxypropyl starch), polyvinyl alcohol, polyvinyl methyl ether,polyethylene oxide, or a cross-linked polyacrylic acid.

Exemplary Aqueous Ophthalmic Solutions

The aqueous ophthalmic solutions having been generally described abovewill now be more specifically described by reference to the followingmore specific examples. The following more specific examples are onlyexemplary and are not intended to limit the scope of the invention inany way.

One such exemplary solution is an aqueous ophthalmic solution free of achelating agent comprising: (a) about 0.1% (w/v) to about 2% (w/v) ofphentolamine mesylate; (b) about 1% (w/v) to about 6% (w/v) of at leastone polyol compound selected from the group consisting of is mannitol,glycerol, and propylene glycol; (c) about 1 mM to about 6 mM of analkali metal acetate; and (d) water; wherein the solution has a pH inthe range of 4 to 6 and does not contain a chelating agent.

The aqueous ophthalmic solution may be more specifically definedaccording to the following embodiments. For example, in certainembodiments, the aqueous ophthalmic solution comprises from about 0.25%(w/v) to about 1% (w/v) of phentolamine mesylate. In certainembodiments, the aqueous ophthalmic solution comprises from about 1%(w/v) to about 4% (w/v) mannitol. In certain other embodiments, theaqueous ophthalmic solution comprises 4% (w/v) mannitol. In certainembodiments, the alkali metal acetate is sodium acetate. In certainother embodiments, the aqueous ophthalmic solution comprises 3 mM sodiumacetate. In still other embodiments, the aqueous ophthalmic solutionconsists of (i) about 0.25% (w/v) to about 1% (w/v) of phentolaminemesylate; (ii) about 1% (w/v) to about 6% (w/v) of one or more polyolcompounds selected from the group consisting of mannitol, glycerol, andpropylene glycol; (iii) about 1 mM to about 6 mM of an alkali metalacetate; (iv) acetic acid; and (v) water; wherein the solution has a pHin the range of 4 to 6.

Another such exemplary solution is an aqueous ophthalmic solution freeof a chelating agent comprising: (a) about 0.5% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 1% (w/v) to about 6% (w/v) of atleast one polyol compound selected from the group consisting of ismannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mMof an alkali metal acetate; and (d) water; wherein the solution has a pHin the range of 4.5 to 5.5 and does not contain a chelating agent.

The aqueous ophthalmic solution may be more specifically definedaccording to the following embodiments. For example, in certainembodiments, the aqueous ophthalmic solution comprises from about 1%(w/v) to about 4% (w/v) mannitol. In certain other embodiments, theaqueous ophthalmic solution comprises 4% (w/v) mannitol. In certainembodiments, the alkali metal acetate is sodium acetate. In certainother embodiments, the aqueous ophthalmic solution comprises 3 mM sodiumacetate. In still other embodiments, the aqueous ophthalmic solutionconsists of (i) about 0.5% (w/v) to about 2% (w/v) of phentolaminemesylate; (ii) about 1% (w/v) to about 6% (w/v) of one or more polyolcompounds selected from the group consisting of mannitol, glycerol, andpropylene glycol; (iii) about 1 mM to about 6 mM of an alkali metalacetate; (iv) acetic acid; and (v) water; wherein the solution has a pHin the range of 4.5 to 5.5.

Another such exemplary solution is an aqueous ophthalmic solution freeof a chelating agent comprising: (a) about 0.25% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 1% (w/v) to about 6% (w/v) of atleast one polyol compound selected from the group consisting of ismannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mMof an alkali metal acetate; and (d) water, wherein the solution has a pHin the range of 4.5 to 5.5 and does not contain a chelating agent.

The aqueous ophthalmic solution may be more specifically definedaccording to the following embodiments. For example, in certainembodiments, the aqueous ophthalmic solution comprises from about 0.25%(w/v) to about 1% (w/v) of phentolamine mesylate. In certain otherembodiments, the aqueous ophthalmic solution comprises from about 1%(w/v) to about 4% (w/v) mannitol. In certain other embodiments, theaqueous ophthalmic solution comprises 4% (w/v) mannitol. In certainembodiments, the alkali metal acetate is sodium acetate. In certainother embodiments, the aqueous ophthalmic solution comprises 3 mM sodiumacetate. In still other embodiments, the aqueous ophthalmic solutionconsists of (i) about 0.5% (w/v) to about 1% (w/v) of phentolaminemesylate; (ii) about 1% (w/v) to about 6% (w/v) of one or more polyolcompounds selected from the group consisting of mannitol, glycerol, andpropylene glycol; (iii) about 1 mM to about 6 mM of an alkali metalacetate; (iv) acetic acid; and (v) water; wherein the solution has a pHin the range of 4.5 to 5.5.

Further exemplary aqueous ophthalmic solutions are provided in Tables1-3 below, where in each instance the solution has a pH in the range of4.7 to 5.1.

TABLE 1 EXEMPLARY AQUEOUS OPHTHALMIC SOLUTIONS. Formulation No.Component A1 B1 C1 D1 E1 F1 G1 H1 Phentolamine mesylate 1.5 1 0.5 1 1 11 1 (% w/v) Mannitol (% w/v) 4 4 4 3 3 2 2 4 Sodium acetate (mM) 3 3 3 33 3 3 3 Glycerol (% w/v) 0 0 0 0.5 0 1 0 0 Propylene glycol 0 0 0 0 0.50 1 0 (% w/v) Dextran 70 (% w/v) 0 0 0 0 0 0 0 0.1 Water q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s.

TABLE 2 EXEMPLARY AQUEOUS OPHTHALMIC SOLUTIONS. Formulation No.Component A2 B2 C2 D2 E2 F2 Phentolamine mesylate 0.25 0.25 0.25 0.250.25 0.25 (% w/v) Mannitol (% w/v) 4 3 3 2 2 4 Sodium acetate (mM) 3 3 33 3 3 Glycerol (% w/v) 0 0.5 0 1 0 0 Propylene glycol 0 0 0.5 0 1 0 (%w/v) Dextran 70 (% w/v) 0 0 0 0 0 0.1 Water q.s. q.s. q.s. q.s. q.s.q.s.

TABLE 3 EXEMPLARY AQUEOUS OPHTHALMIC SOLUTIONS. Formulation No.Component A3 B3 C3 D3 E3 F3 G3 H3 Phentolamine mesylate 1.5 1 0.5 0.25 11 1 1 (% w/v) Mannitol (% w/v) 4 4 4 4 3 2 2 4 Sodium acetate (mM) 3 3 33 3 3 2 3 Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.

Another exemplary aqueous ophthalmic solution comprises phentolaminemesylate (e.g., at 1% w/v), mannitol (e.g., at 4% w/v), dextran having aweight average molecular weight of about 70,000 g/mol (e.g., at 0.1%w/v), hydroxypropyl methylcellulose (e.g., at 0.3% w/v), potassiumchloride, purified water, sodium borate, and sodium chloride; whereinthe solution has a pH in the range of about 4 to about 6. In certainembodiments, the solution has a pH in the range of 4.5 to 5.1. Incertain embodiments, the aqueous ophthalmic solution consistsessentially of phentolamine mesylate (e.g., at 1% w/v), mannitol (e.g.,at 4% w/v), dextran having a weight average molecular weight of about70,000 g/mol (e.g., at 0.1% w/v), hydroxypropyl methylcellulose (e.g.,at 0.3% w/v), potassium chloride, purified water, sodium borate, andsodium chloride; wherein the solution has a pH in the range of 4 to 6.In certain other embodiments, the aqueous ophthalmic solution consistsof phentolamine mesylate (e.g., at 1% w/v), mannitol (e.g., at 4% w/v),dextran having a weight average molecular weight of about 70,000 g/mol(e.g., at 0.1% w/v), hydroxypropyl methylcellulose (e.g., at 0.3% w/v),potassium chloride, purified water, sodium borate, and sodium chloride;wherein the solution has a pH in the range of 4.5 to 5.1.

Another exemplary aqueous ophthalmic solution comprises phentolaminemesylate (e.g., at 1% w/v), mannitol (e.g., at 4% w/v), sodium acetate(e.g., at 3 mM), and water, wherein the solution has a pH in the rangeof about 4 to about 6. In certain embodiments, the solution has a pH inthe range of 4.5 to 5.1. In certain embodiments, the aqueous ophthalmicsolution consists essentially of phentolamine mesylate (e.g., at 1%w/v), mannitol (e.g., at 4% w/v), sodium acetate (e.g., at 3 mM), andwater, wherein the solution has a pH in the range of 4 to 6. In certainembodiments, the aqueous ophthalmic solution comprises phentolaminemesylate at 1% w/v, mannitol 4% w/v, sodium acetate at 3 mM, and water,wherein the solution has a pH in the range of 4.5 to 5.1. In certainother embodiments, the aqueous ophthalmic solution consists ofphentolamine mesylate (e.g., at 1% w/v), mannitol (e.g., at 4% w/v),sodium acetate (e.g., at 3 mM), and water, wherein the solution has a pHin the range of 4.5 to 5.1. In certain embodiments, the aqueousophthalmic solution consists essentially of phentolamine mesylate at 1%w/v, mannitol 4% w/v, sodium acetate at 3 mM, and water, wherein thesolution has a pH in the range of 4.5 to 5.1.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.1% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 1% (w/v) to about 6% (w/v) of atleast one polyol compound selected from the group consisting of ismannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mMof an alkali metal acetate; and (d) water; wherein the solution has a pHin the range of 4 to 6 and does not contain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.25% (w/v) to about 2%(w/v) of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 2 mM to about 4 mM of sodium acetate; and (d) water;wherein the solution has a pH in the range of 4.6 to 5.2 and does notcontain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.1% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 2 mM to about 4 mM of sodium acetate; and (d) water;wherein the solution has a pH in the range of 4.6 to 5.2 and does notcontain a chelating agent. In certain embodiments, the aqueousophthalmic solution free of a chelating agent that comprises about 0.25%(w/v) to about 1% (w/v) of phentolamine mesylate.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent, comprising: (a) about 0.25% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 2 mM to about 4 mM of sodium acetate; and (d) water;wherein the solution has a pH in the range of 4.5 to 5.2 and does notcontain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.5% (w/v) to about 2% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 2 mM to about 4 mM of sodium acetate; and (d) water;wherein the solution has a pH in the range of 4.6 to 5.2 and does notcontain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent that comprises: (a) about 0.5% (w/v) to about 1% (w/v)of phentolamine mesylate; (b) about 3% (w/v) to about 5% (w/v) ofmannitol; (c) about 1 mM to about 4 mM of sodium acetate; and (d) water;wherein the solution has a pH in the range of 4.6 to 5.2 and does notcontain a chelating agent.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent, comprising: (a) about 0.1% (w/v) to about 1% (w/v) ofphentolamine mesylate; (b) about 4% mannitol; (c) about 3 mM sodiumacetate; and (d) water; wherein the solution has a pH in the range of4.6 to 5.2 and does not contain a chelating agent. In certainembodiments, the aqueous ophthalmic solution free of a chelating agentthat comprises about 0.25% (w/v) to about 1% (w/v) of phentolaminemesylate.

Yet another exemplary solution is an aqueous ophthalmic solution free ofa chelating agent, comprising: (a) about 0.5% (w/v) to about 1% (w/v) ofphentolamine mesylate; (b) about 4% mannitol; (c) about 3 mM sodiumacetate; and (d) water; wherein the solution has a pH in the range of4.6 to 5.2 and does not contain a chelating agent.

Stability Features of Aqueous Ophthalmic Solutions

The aqueous ophthalmic solutions described herein may be furthercharacterized according to their stability features, such as thepercentage of phentolamine (or pharmaceutically acceptable salt thereof)that is present in the aqueous ophthalmic solution after storage for acertain length of time. As explained above, one of the benefits of thepresent aqueous ophthalmic solutions is that they possess good stabilityover extended periods of time, even though they do not have a chelatingagent.

Accordingly, in certain embodiments, the aqueous ophthalmic solution ischaracterized by less than 2% by weight of the phentolamine orpharmaceutically acceptable salt thereof degrades upon storage of thesolution at 25° C. for 12 weeks. In certain other embodiments, theaqueous ophthalmic solution is characterized by less than 2% by weightof the phentolamine or pharmaceutically acceptable salt thereof degradesupon storage at 25° C. for 24 weeks (or 36 weeks or 48 weeks). In yetother embodiments, less than 7% by weight of the phentolamine orpharmaceutically acceptable salt thereof degrades upon storage at 40° C.for 12 weeks (or 24, 36, or 48 weeks). In yet other embodiments, theaqueous ophthalmic solution is characterized by less than 10% by weightof the phentolamine or pharmaceutically acceptable salt thereof degradesupon storage at 25° C. for 18 months, 24 months, or 36 months. In yetother embodiments, the aqueous ophthalmic solution is characterized byless than 10% by weight of the phentolamine or pharmaceuticallyacceptable salt thereof degrades upon storage at temperature in therange of 2-8° C. for 18 months, 24 months, or 36 months. In yet otherembodiments, the aqueous ophthalmic solution is characterized by lessthan 4% by weight (or preferably less than 3% by weight) of thephentolamine or pharmaceutically acceptable salt thereof degrades uponstorage at 25° C. for 18 months, 24 months, or 36 months. In yet otherembodiments, less than 10% by weight of the phentolamine orpharmaceutically acceptable salt thereof degrades upon storage at 40° C.for 4, 5, or 6 months.

Polyvinylpyrrolidone Artificial Tears Formulation

Another ophthalmic solution contemplated for use in the presentinvention includes, polyvinylpyrrolidone artificial tears formulations,such as those described in, for example, U.S. Pat. Nos. 5,895,654;5,627,611; and 5,591,426; and U.S. Patent Application Publication No.2002/0082288, all of which are hereby incorporated by reference.Artificial tears formulations are understood to promote wettability andspread, have good retention and stability on the eye, and desirably donot cause any significant discomfort to the user. Accordingly, anexemplary polyvinylpyrrolidone artificial tear composition comprises:(1) polyvinylpyrrolidone, preferably in the amount of about 0.1-5% byweight of the solution; (2) benzalkonium chloride, preferably in anamount of about 0.01-0.10%° by weight of the solution; (3) hydroxypropylmethylcellulose, preferably in an amount of about 0.2-1.5% by weight ofthe solution; (4) glycerin, preferably in an amount of about 0.2-1.0% byweight of the solution, and (5) water, wherein the pharmaceuticalcomposition is an aqueous solution having isotonic properties.

III. Medical Kits

Another aspect of the invention provides a medical kit comprising, forexample, (i) an ophthalmic solution described herein, and (ii)instructions for administering the ophthalmic solution according tomethods described herein.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustrating certain aspects and embodiments ofthe present invention, and are not intended to limit the invention.

Example 1

A clinical study was performed in which phentolamine mesylate wasadministered to eyes of patients suffering from severe night visiondifficulty. Experimental procedures and results are described below.

Part I—Experimental Procedures

Sixty patients with normal day vision (i.e., 20/40 or better) but whichsuffer from severe night vision difficulty were enrolled in the study.During the first period of the study, patients were randomized intothree groups. The groups received either placebo, 0.5% (w/v)phentolamine mesylate, or 1.0% (w/v) phentolamine mesylate once dailyfor 15 days. The patients were observed on days 1, 4, 8, and 15 prior toadministering the ophthalmic solution of phentolamine mesylate and thenobserved again two hours after the ophthalmic solution of phentolaminemesylate was administered. During the second period of the study, allsixty patients were instructed to administer an ophthalmic solution ofphentolamine mesylate (1% (w/v)) as needed, but no more than once dailyto each eye. The ophthalmic solution of phentolamine mesylate contained:1% (w/v) phentolamine mesylate, 4% (w/v) mannitol, 3 mM sodium acetate,and water. The placebo was a solution containing 4% (w/v) mannitol, 3 mMsodium acetate, and water.

Patients in the study satisfied the following criteria: (1) 18-45 yearsof age and suffer from severe night vision difficulty, (2) 0.3 logimprovement at two of five spatial frequencies (1.5, 3, 6, 12, and 18cycles per degree) in at least one eye before and during illumination ofthe contralateral eye, using the Holladay Automated Contrast SensitivitySystem test under mesopic room illumination with glare, and (3) photopicdistance high-contrast visual acuity (corrected or uncorrected) of 20/40or better in at least one eye.

Patients were to meet with a clinician for evaluation on study days 1,4, 8, 15, and a post-dosing follow-up evaluation three or more daysafter administering the last dose in the second period. When patientsmet with the clinician, the following observations were made by theclinician: (1) mesopic contrast sensitivity with and without glare usingthe Holladay Automated Contrast Sensitivity System test, (2) mesopicdistance high-contrast visual acuity using E-ETDRS Acuity Testing, (3)mesopic distance low-contrast visual acuity using E-ETDRS AcuityTesting, (4) photopic distance high-contrast visual acuity using E-ETDRSAcuity Testing, and (5) eye redness using the Cornea and Contact LensResearch Unit (CCLRU) Redness Grading Scale developed by the School ofOptometry, University of New South Wales, but that the grading scale wasas follows: (0) none, (0.5) very slight, (1) slight, (2) moderate, and(3) severe.

The primary efficacy endpoint is an increase of at least 0.3 log (50% ormore improvement) in mesopic contrast sensitivity with glare at two ormore frequencies at 1.5, 3, 6, 12, and 18 cycles per degree, measuredwith Holladay Automated Contrast Sensitivity System methodology.

Part II—Results

Results from the study are depicted in FIGS. 1-10. FIG. 1 shows that,beginning with day 8 of the study, greater than 20% of eyes tested afterdaily administration of phentolamine mesylate showed at least a 50%improvement in the contrast sensitivity measurement relative tobaseline. FIG. 2 shows that, beginning with day 8 of the study, greaterthan 20% of eyes tested prior to administration of phentolamine mesylateon that day showed at least a 50% improvement in the contrastsensitivity measurement relative to baseline. Further, the data in FIGS.1 and 2 show that no diminution in efficacy was observed with repeateddosing of phentolamine mesylate during the 15-day study period.

FIG. 3 shows that the percentage of eyes with at least a 50% improvementcontrast sensitivity measured prior to that day's administration ofphentolamine mesylate increased from day 15 to day 32 of the study. FIG.4A is a bar graph showing the percentage of eyes with at least a 50%improvement in contrast sensitivity after the last dose of phentolaminemesylate during the second period of the study. Data in FIG. 4Ademonstrates that the dosing protocol using phentolamine mesylateresulted in a pharmacokinetic half-life of approximately two days. FIG.4B is a bar graph showing the percentage of eyes with at least a 10%reduction in pupil diameter after the last dose of phentolamine mesylateduring the second period of the study. Data in FIG. 4B furtherdemonstrates that the dosing protocol using phentolamine mesylateresulted in a pharmacokinetic half-life of approximately two days.

FIG. 5 is a line graph depicting the results from eye rednessmeasurements. FIG. 5 shows that eye redness increases immediately afteradministration of the phentolamine mesylate, but that the eye rednesssubsides (i.e., returns to baseline) when measured prior to phentolaminemesylate administration on days 4, 8, and 15.

FIGS. 6 and 7 are bar graphs showing the percentage of eyes thatdemonstrated improvement in visual acuity as measured using a Snellenchart. FIG. 8 depicts bar graphs showing the mean VFQ Improvement Scoreon day 32 of the study in subjects with ≥50% vs. <50% improvement incontrast sensitivity. FIGS. 9 and 10 are line graphs showing theobserved reduction in pupil diameter. FIG. 9 shows the reduction inpupil diameter relative to baseline when measured two hours after thatday's administration of phentolamine mesylate. FIG. 10 shows thereduction in pupil diameter relative to baseline when measured prior tothat day's administration of phentolamine mesylate.

Example 2

A clinical study was performed in which a phentolamine mesylate solutionwas administered to eyes of patients that were at least 18 years old andhad a clinical history of pupil sizes of at least 7 mm in diameter underdim light conditions. The phentolamine mesylate solution containedeither 0.2% (w/v) phentolamine mesylate, 0.4% (w/v) phentolaminemesylate, or 0.8% (w/v) phentolamine mesylate. Experimental proceduresand results are described below.

Part I—Experimental Procedures

Sixteen patients were randomized into four groups (of four subjectseach). Each group was treated on three successive study visits separatedby at least 4 days with one drop of ophthalmic oxymetazoline solution(Visine LR®) in each eye followed by one drop test article in each eye.The test article was a 0.2% (w/v) phentolamine mesylate solution, 0.4%(w/v) phentolamine mesylate solution, 0.8% (w/v) phentolamine mesylatesolution, or placebo. Test articles contained the designed amount ofphentolamine mesylate in a solution of Tears Naturale II® (from AlconLabs). Placebo was just Tears Naturale II® (from Alcon Labs). TearsNaturale II® (from Alcon Labs) contains Dextran 70 (0.1% by weight),Hydroxypropyl Methylcellulose 2910 (0.3% by weight), Polyquarternium-1(0.001% by weight), potassium chloride, water (purified), sodium borate,sodium chloride, and hydrochloric acid and/or sodium hydroxide asnecessary to adjust the pH. The patients' eye redness and pupildiameters were recorded at baseline (i.e., prior to treatmentadministration), and at 30 minutes, 1 hour, 2 hours, 4 hours, and 8hours after administration of test articles. The incidence of anytreatment-emergent adverse events was also recorded. Total studyduration was approximately nine hours. Treatment group randomizationschedules are provided in Table 1 below.

TABLE 1 TREATMENT GROUP RANDOMIZATION SCHEDULES Visit 1 Treatment Visit2 Treatment Visit 3 Treatment Group 1 0.2% (w/v) 0.4% (w/v) 0.8% (w/v)(N = 4) phentolamine phentolamine phentolamine mesylate solutionmesylate solution mesylate solution Group 2 0.2% (w/v) 0.4% (w/v)placebo (N = 4) phentolamine phentolamine mesylate solution mesylatesolution Group 3 0.2% (w/v) placebo 0.8% (w/v) (N = 4) phentolaminephentolamine mesylate solution mesylate solution Group 4 placebo 0.4%(w/v) 0.8% (w/v) (N = 4) phentolamine phentolamine mesylate solutionmesylate solution

Patients were eligible for enrollment if they were (a) at least 18 yearsof age, and (b) had a documented pupil size in dim light of greater than7 mm. Patients were ineligible for enrollment in the study if they metany of the following criteria: (a) had moderate to severe hypertension,(b) had a history of heart rate abnormalities, (c) had been administeredany investigational drug within 14 days of screening, (d) had a knownlocal or systemic hypersensitivity to adrenergic antagonists, or (e) hadcentral corneal pathology.

Eye redness of patients' eyes was evaluated by the research assistantand recorded as a single integer of value 0 (no redness) to 4 (extremeredness) at baseline and each time point after treatment. Pupildiameters were measured to within 0.1 mm for each eye at baseline andeach subsequent time point using a NeurOptics™ pupilometer. Monocularhigh contrast visual acuity was measured for each eye under photopicconditions at baseline and each subsequent time point in a darkened roomusing a Precision Vision™ High Contrast (100% tint) Visual Acuity Chart(Catalog #2102) backlit by the Precision Vision Illumination Box.Monocular low contrast visual acuity was measured for each eye underphotopic conditions at baseline and each subsequent time point in adarkened room using a Precision Vision™ Low Contrast (5% tint) VisualAcuity Chart (Catalog #2186) backlit by the Precision VisionIllumination Box. Effect of treatment on glare was assessed using anexperimental test method consisting of a panel with a high wattagecentral light emitting diode (LED) and a set of 7 lower wattage red LEDsradiating horizontally and vertically from the central light.

Comparisons of changes in mean values within treatment groups weretested for significance using two-tailed paired two sample t-tests witha threshold for significance set at p<0.01 (Bonferroni Correction formultiple paired t-tests). Differences between treatment groups withrespect to mean values for pupil size over the course of the study weretested for significance using repeated measure ANOVA (which discardsdata from subjects lacking any data points). Differences in mean eyeredness between treatment groups were evaluated using Kruskal-Wallisnonparametric testing. Differences in means between treatment groups atindividual time points were tested for significance using one-way ANOVA.If one-way ANOVA showed significance at a given time point, ad hocFisher's testing was performed to identify significant differencesbetween individual group means.

Part II—Results

Fifteen of 16 patients completed the study. One patient randomized toGroup 3 completed only two of three clinic visits, missing the 0.8%(w/v) phentolamine mesylate dose. The results of pupil measurements,visual acuity testing, and eye redness are described below.

Pupil Measurements

One criterion for entrance into the study was historical documentationof a pupil size >7 mm when measured under dim light conditions. Table 2provides the mean pupil diameters, standard deviation of pupildiameters, and the observed range of diameters recorded immediatelyprior to administration of each treatment.

TABLE 2 BASELINE PUPIL MEASURES 0.2% (w/v) 0.4% (w/v) 0.8% (w/v)Phentol- Phentol- Phentol- Pupil amine amine amine Variable PlaceboMesylate Mesylate Mesylate Sample Size^(a) 24 24 24 22^(b)   Mean 7.87.8 7.7 8.0 Diameter (mm) Standard 0.6 0.9 0.7 1.1 Deviation (mm) Range(mm) 6.5-8.7 5.2-8.8 5.8-8.6 4.6-9.3 ^(a)measurements from each pupiltreated separately ^(b)one subject missed the 0.8% phentolamine dosingvisit

Average baseline pupil diameters were comparable across all fourtreatment groups, with observed differences in means (Table 2) notstatistically significant (P=0.766). Of the 94 baseline pupil diameterscollected during the study, there were twelve instances (representing 3subjects; Table 3) in which baseline pupil diameters were less than theinclusion criterion of 7 mm. Baseline pupil diameters less than 7 mmwere evenly distributed between treatment groups (2, 3, 4, and 3 pupilsin Placebo, 0.2%, 0.4%, and 0.8% (w/v) phentolamine mesylate treatmentgroups, respectively).

TABLE 3 SUBJECTS WITH BASELINE PUPIL DIAMETERS LESS THAN 7 MM Subject 2Subject 6 Subject 16 Study Right Pupil Left Pupil Right Pupil Left PupilRight Pupil Left Pupil Visit (mm) (mm) (mm) (mm) (mm) (mm) 1 6.7 7.1 7 75.8 5.7 2 6.7 6.5 6.8 6.3 6.3 5.8 3 7.9 8.2 7.4 6.7 5.5 4.6

For all study groups, mean pupil diameters were relatively unchanged at30 minutes after treatment. By one hour post treatment, mean pupildiameters were lower (P=0.47) for phentolamine-treated subjects. Meanpupil diameters for subjects receiving placebo were relatively constantfor the 8 hours of post-treatment observation.

TABLE 4 MEAN PUPIL DIAMETERS DURING THE STUDY 30 1 2 4 8 TreatmentGroup^(a) Baseline min hour hours hours hours Placebo Mean Diameter (mm)7.83 7.87 7.80 7.93 7.87 8.08^(b) Standard Deviation 0.61 0.81 0.79 0.600.58 0.75 Minimum (mm) 6.5 5.5 5.9 6.5 6.8 6.5 Maximum (mm) 8.7 9.0 9.29.0 9.0 9.3 0.2% (w/v) Phentolamine Mesylate Mean Diameter (mm) 7.787.74 7.54 7.01^(c) 7.30^(d) 7.18 Standard Deviation 0.88 1.02 1.02 0.820.51 0.90 Minimum (mm) 5.2 5.1 4.9 4.7 6.3 4.7 Maximum (mm) 8.8 9.2 8.98.4 8.0 8.5 0.4% (w/v) Phentolamine Mesylate Mean Diameter (mm) 7.717.72 7.41 7.05 7.01 7.01 Standard Deviation 0.71 0.81 0.77 0.84 0.920.97 Minimum (mm) 5.8 5.6 5.5 5.0 5.0 4.8 Maximum (mm) 8.6 8.8 8.3 8.48.1 8.6 0.8% (w/v) Phentolamine Mesylate ^(e) Mean Diameter (mm) 7.967.87 7.69 7.30 7.32 7.40 Standard Deviation 1.10 0.97 0.97 0.99 0.990.99 Minimum (mm) 4.6 5.2 5.1 4.7 5.5 4.7 Maximum (mm) 9.3 9.2 9.1 8.78.6 8.7 ^(a)24 pupils per sample except where noted ^(b)20 pupils; 8hour data for subjects 2 and 11, visit 2, were not recorded ^(c)22pupils; 2 hour data from subject 7, visit 1 not recorded ^(d)22 pupils;4 hour data from subject 16, visit 1 not recorded ^(e) 22 pupils at eachtime point, subject 16 missed visit 3

Repeated measures ANOVA showed a significant (p<0.001) differencebetween treatment groups with respect to pupil diameter over the courseof the study. Significant differences in mean pupil diameters betweentreatment were identified by one-way ANOVA at 2 hours (p=0.0006), 4hours (p=0.0027) and 8 hours (p=0.0016) after treatment. Ad hoc Fisher'stests of significance between individual group means demonstratedsignificant differences in mean pupil diameters of subjects treated withany concentration of phentolamine mesylate when compared to placebo at2, 4 and 8 hours (Table 5). In contrast, there were no statisticallysignificant differences in mean pupil diameters observed betweendifferent doses of phentolamine at any time point.

TABLE 5 SIGNIFICANCE OF DIFFERENCES BETWEEN MEAN PUPIL DIAMETERSTreatment Comparison 2 hours 4 hours 8 hours Placebo vs. 0.2% (w/v) P =0.0003 P = 0.0147 P = 0.0018 Phentolamine Mesylate Placebo vs. 0.4%(w/v) P = 0.0003 P = 0.0002 P = 0.0002 Phentolamine Mesylate Placebo vs.0.8% (w/v) P = 0.0110 P = 0.0200 P = 0.0199 Phentolamine Mesylate *Fisher's Ad Hoc test of means for time points previously shown to besignificant by One-Way ANOVA

For all treatment groups, mean pupil diameters were relatively unchangedfrom baseline at 30 minutes after treatment (Table 6). By one hour posttreatment, change from baseline in mean pupil diameters was significant(p<0.01) for subjects treated with 0.2% (w/v), 0.4% (w/v), and 0.8%(w/v) phentolamine mesylate. Mean pupil diameters did not significantlychange from baseline for subjects receiving placebo over the 8 hours ofpost-treatment observation.

Differences in mean pupil diameters of treatment groups are expressed asmean changes in diameter from baseline in Table 6. When mean changes inpupil diameters from baseline are evaluated as a function of time, it isapparent that those subjects receiving phentolamine mesylate experiencedsignificant reductions in pupil size over the course of the study.

TABLE 6 MEAN PUPIL DIAMETER CHANGES FROM BASELINE OVER TIME 30 1 2 4 8Treatment Group min hour hours hours hours Placebo Mean Change (mm) 0.04−0.03 0.10 0.04 0.12 Standard Deviation 0.32 0.36 0.34 0.51 0.35 SampleSize (pupils) 24 24 24 24 20 P- value^(a) 0.57 0.66 0.15 0.72 0.15 0.2%(w/v) Phentolamine Mesylate Mean Change (mm) −0.04 −0.24 −0.75 −0.69−0.59 Standard Deviation 0.33 0.37 0.51 0.49 0.62 Sample Size (pupils)24 24 22 22 24 P- value^(a) 0.58 <0.005 <0.001 <0.001 <0.001 0.4% (w/v)Phentolamine Mesylate Mean Change (mm) 0.00 −0.29 −0.64 −0.74 −0.74Standard Deviation 0.40 0.33 0.46 0.45 0.47 Sample Size (pupils) 22 2222 22 22 P- value^(a) 0.86 <0.001 <0.001 <0.001 <0.001 0.8% (w/v)Phentolamine Mesylate Mean Change (mm) −0.10 −0.27 −0.66 −0.64 −0.56Standard Deviation 0.31 0.43 0.44 0.61 0.43 Sample Size (pupils) 22 2222 22 22 P- value^(a) 0.16 <0.007 <0.001 <0.001 <0.001 ^(a)Two-sidedpaired two-sample t-test. P < 0.01 is significant by BonferronicorrectionVisual Acuity

Mean values for best corrected high-contrast visual acuity were notstatistically significantly different between treatment groups atbaseline, with Log Mar values ranging from 0.04 to 0.08 (Table 7),equivalent of a range of 20/16 to 20/18 vision. Despite the observationthat mean baseline high contrast visual acuities were above “normal”(i.e., better than 20/20) for all treatment groups, mean acuityincreased for all groups 30 minutes after treatment and mean acuitiesremained elevated above baseline throughout the 8-hour observationperiod (Table 7). Two-sided paired two-sample t-tests of visual acuitiescompared to baseline showed that all treatment groups (includingplacebo) with the exception of 0.8% (w/v) phentolamine mesylate had atleast one time point after treatment in which visual acuities weresignificantly elevated relative to baseline (bolded P values of Table7).

TABLE 7 EFFECTS ON HIGH CONTRAST VISUAL ACUITY 30 1 2 4 8 TreatmentGroup^(a) Baseline Min hour hour hours hours Placebo Mean acuity(LogMar) 0.08 0.10 0.13 0.12 0.12 0.11^(b) Standard Deviation 0.11 0.090.08 0.09 0.07 0.08 Minimum (LogMar) −0.15 −0.10 −0.02 −0.10 −0.02 −0.10Maximum (LogMar) 0.26 0.26 0.30 0.30 0.22 0.22 P- value^(c) 0.612 0.0200.003 0.014 0.087 0.2% (w/v) Phentolamine Mesylate Mean acuity (LogMar)0.04 0.05 0.08 0.08 0.09 0.08 Standard Deviation 0.13 0.14 0.12 0.120.12 0.13 Minimum (LogMar) −0.32 −0.32 −0.20 −0.22 −0.20 −0.32 Maximum(LogMar) 0.22 0.22 0.22 0.26 0.22 0.22 P- value^(c) 0.612 0.020 0.0030.001 0.002 0.4% (w/v) Phentolamine Mesylate Mean acuity (LogMar) 0.090.12 0.11 0.14 0.15 0.13 Standard Deviation 0.11 0.09 0.11 0.10 0.090.11 Minimum (LogMar) −0.24 −0.20 −0.20 −0.10 −0.11 −0.18 Maximum(LogMar) 0.22 0.22 0.26 0.30 0.30 0.30 P- value^(c) 0.002 0.147 0.0010.001 0.010 0.8% (w/v) Phentolamine Mesylate ^(d) Mean acuity (LogMar)0.06 0.11 0.12 0.12 0.12 0.13 Standard Deviation 0.15 0.11 0.11 0.120.14 0.13 Minimum (LogMar) −0.41 −0.16 −0.10 −0.16 −0.20 −0.20 Maximum(LogMar) 0.22 0.22 0.26 0.30 0.30 0.30 P- value^(c) 0.126 0.061 0.0430.054 0.039 ^(a)12 subjects, 24 eyes per treatment group except wherenoted ^(b)Mean of 10 subjects, 20 eyes ^(c)Two-sided paired two-samplet-test compared to baseline. P < 0.01 is significant by Boneferronicorrection ^(d) Mean of 11 subjects, 22 eyes

A trend (P=0.16) towards phentolamine dose-proportionality in highcontrast visual acuity improvement was observed by repeated measuresANOVA. This trend in high contrast vision improvement was modest, with amaximal mean increase of 0.06 Log Mar at 4 and 8 hours for subjectstreated with 0.8% phentolamine, roughly equating to an improvement invision of 3 letters on a Snellen chart.

Mean values for best corrected low contrast visual acuity were notstatistically significantly different between treatment groups atbaseline, with Log Mar values ranging from −0.34 to −0.28 (Table 8),roughly equivalent to a range of 20/38 to 20/44 vision. Mean lowcontrast acuity increased for all groups 30 minutes after treatment(Table 8). Beyond 30 minutes, there was strong evidence of phentolaminedose-proportionality with respect to improvement in mean low contrastvisual acuity. Treatment with 0.8% (w/v) phentolamine mesylate resultedin significant increases in mean low contrast acuity at allpost-treatment time points compared to baseline, as did treatment with0.4% (w/v) phentolamine mesylate at 1, 2, 4, and 8 hours post treatment(two-sided paired two-sample t-test; bolded P values of Table 8).

TABLE 8 EFFECTS ON LOW CONTRAST VISUAL ACUITIES 30 1 2 4 8 TreatmentGroup^(a) Baseline min hour hours hours hours Placebo Mean acuity(LogMar) −0.29 −0.28 −0.27 −0.27 −0.25 −0.30^(b) Standard Deviation 0.130.10 0.11 0.10 0.09 0.07 Minimum (LogMar) −0.64 −0.50 −0.60 −0.50 −0.40−0.42 Maximum (LogMar) −0.11 −0.11 −0.11 −0.10 −0.10 −0.20 P value^(c)0.230 0.189 0.192 0.022 0.710 0.2% (w/v) Phentolamine Mesylate Meanacuity (LogMar) −0.34^(d) −0.35 −0.32 −0.32 −0.30 −0.30^(e) StandardDeviation 0.18 0.19 0.18 0.17 0.20 0.19 Minimum (LogMar) −0.80 −0.78−0.80 −0.74 −0.76 −0.72 Maximum (LoeMar) −0.06 −0.10 −0.08 −0.11 0.00−0.08 P value^(c) 0.724 0.060 0.198 0.111 0.026 0.4% (w/v) PhentolamineMesylate Mean acuitv (LogMar) −0.28 −0.24 −0.24 −0.22 −0.20 −0.22Standard Deviation 0.13 0.15 0.17 0.14 0.16 0.15 Minimum (LogMar) −0.74−0.70 −0.78 −0.64 −0.70 −0.64 Maximum (LogMar) −0.10 0.00 −0.04 0.000.00 0.00 P value^(c) 0.011 0.006 0.001 0.001 0.001 0.8% (w/v)Phentolamine Mesylate^(e) Mean acuity (LogMar) −0.34 −0.28 −0.25 −0.22−0.22 −0.25 Standard Deviation 0.16 0.16 0.15 0.15 0.17 0.19 Minimum(LogMar) −0.78 −0.76 −0.62 −0.60 −0.70 −0.78 Maximum (LogMar) −0.11−0.02 0.00 0.00 0.00 0.00 P value^(c) 0.001 0.001 0.001 0.001 0.001^(b)12 subjects, 24 eyes per treatment group except where noted ^(c)Meanof 10 subjects, 20 eyes ^(d)Two-sided paired two-sample t-test comparedto baseline. P < 0.01 is significant by Bonferroni correction ^(e)Meanof 12 subjects, 23 eyes (one entry missing on CRF) f - Mean of 11subjects, 22 eyes

Statistically-significant (P=0.0091) different changes in low contrastvisual acuity between groups were observed in the study by repeatedmeasures ANOVA). One-way ANOVA at each time point identified significantdifferences between mean low contrast visual acuities at 2 hourspost-dosing, and ad hoc Fisher's testing identified significantdifferences between 0.2% (w/v) phentolamine treatment and both 0.4%(w/v) phentolamine mesylate and 0.8% (w/v) phentolamine mesylatetreatment (P<0.05). The magnitude of low contrast vision improvement wasrelatively modest, with a maximal mean increase of 0.12 Log Mar at 2hours for subjects treated with 0.8% (w/v) phentolamine mesylate roughlyequating to an improvement in vision of 6 letters on a Snellen chart.

Eye Redness

Eye redness was recorded on an integer scale of 0 (least) to 4 (most)redness at each time point collected. Mean eye redness at baseline(Table 9) was not statistically different between treatment groups(P=0.6625; Kruskal-Wallis nonparametric analysis). Over the course ofthe study, mean eye redness for subjects treated with 0.2% (w/v)phentolamine mesylate did not differ from placebo. Subjects treated witheither 0.4% (w/v) or 0.8% (w/v) phentolamine mesylate experienced amodest increase in eye redness at 2 and 4 hours post treatment, whichregressed by 8 hours. Differences in mean eye redness between treatmentgroups were only significant (P=0.0152; Kruskal-Wallis nonparametricanalysis) at 4 hours post treatment. FIG. 12 is a line graph showing eyeredness as a function of time, whereby eye redness returns to baselinewithin 8 hours after administration of phentolamine mesylate.

TABLE 9 MEAN EYE REDNESS SCORES 30 1 2 4^(b) 8 Treatment Group^(a)Baseline min hour hours hours hours Placebo Mean Score 0.17 0.08 0.080.08 01^(b)   0^(b)   Standard Deviation 0.39 0.29 0.29 0.29 0   0  Range 0-1 0-1 0-1 0-1 0-0 0-0 0.2% (w/v) Phentolamine Mesylate MeanScore 0.00 0.17 0.08 0.17  0.18^(b)  0.09^(b) Standard Deviation 0.000.39 0.29 0.39 0.40 0.30 Range 0-1 0-1 0-1 0-1 0-1 0-1 0.4% (w/v)Phentolamine Mesylate ^(c) Mean Score 0.25 0.33 0.50 0.50 0.58 0.00Standard Deviation 0.45 0.49 0.67 0.67 0.67 0.00 Range 0-1 0-1 0-2 0-20-2 0-0 0.8% (w/v) Phentolamine Mesylate Mean Score 0.18 0.27 0.36 0.640.45 0.27 Standard Deviation 0.40 0.47 0.67 1.03 0.52 0.47 Range 0-1 0-10-2 0-3 0-1 0-1 ^(a)12 subjects per group except where noted^(b)Significant (P = 0.0152) differences between groups byKruskal-Wallis nonparametric analysis ^(c) data from 11 subjects

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

I claim:
 1. A method of improving visual performance in a patient whileminimizing eye redness during the patient's waking hours, comprisingadministering to an eye of a patient once per day at or near the bedtimeof the patient for at least five consecutive days a daily dosage ofphentolamine or a pharmaceutically acceptable salt thereof sufficient toprovide improved visual performance for at least twenty hours, whereinthe patient experiences an increase in eye redness of no more than twogrades measured using the CCLRU Redness Grading Scale during thepatient's waking hours compared to the patient's level of eye rednesswithout receiving said dosage; wherein the daily dosage is an aqueousophthalmic solution comprising from about 0.5% (w/v) to about 2% (w/v)of phentolamine or a pharmaceutically acceptable salt thereof that isadministered to the eye in the form of an eye drop, and the patient is ahuman.
 2. The method of claim 1, wherein the daily dosage isadministered for at least seven consecutive days.
 3. The method of claim1, wherein the improvement in visual performance is improved visualacuity.
 4. The method of claim 1, wherein the improvement in visualperformance is improved contrast sensitivity.
 5. The method of claim 1,wherein the patient experiences an increase in eye redness of no morethan one grade measured using the CCLRU Redness Grading Scale during thepatient's waking hours compared to the patient's level of eye rednesswithout receiving said dosage.
 6. A method of reducing pupil diameter ina patient while minimizing eye redness during the patient's wakinghours, comprising administering to an eye of a patient once per day ator near the bedtime of the patient for at least five consecutive days adaily dosage of phentolamine or a pharmaceutically acceptable saltthereof sufficient to reduce pupil diameter for at least twenty hours,wherein the patient experiences an increase in eye redness of no morethan two grades measured using the CCLRU Redness Grading Scale duringthe patient's waking hours compared to the patient's level of eyeredness without receiving said dosage; wherein the daily dosage is anaqueous ophthalmic solution comprising from about 0.5% (w/v) to about 2%(w/v) of phentolamine or a pharmaceutically acceptable salt thereof thatis administered to the eye in the form of an eye drop, and the patientis a human.
 7. A method of reducing an aberrant focus of scattered lightrays in a patient's eye while minimizing eye redness during thepatient's waking hours, comprising administering to an eye of a patientonce per day at or near the bedtime of the patient for at least fiveconsecutive days a daily dosage of phentolamine or a pharmaceuticallyacceptable salt thereof sufficient to reduce aberrant focus of scatteredlight rays in a patient's eye for at least twenty hours, wherein thepatient experiences an increase in eye redness of no more than twogrades measured using the CCLRU Redness Grading Scale during thepatient's waking hours compared to the patient's level of eye rednesswithout receiving said dosage; wherein the daily dosage is an aqueousophthalmic solution comprising from about 0.5% (w/v) to about 2% (w/v)of phentolamine or a pharmaceutically acceptable salt thereof that isadministered to the eye in the form of an eye drop, and the patient is ahuman.
 8. The method of claim 7, wherein the daily dosage isadministered for at least seven consecutive days.
 9. The method of claim6, wherein the patient experiences an increase in eye redness of no morethan one grade measured using the CCLRU Redness Grading Scale during thepatient's waking hours compared to the patient's level of eye rednesswithout receiving said dosage.
 10. The method of claim 6, wherein thedaily dosage is administered within 1 hour of the patient's bedtime. 11.The method of claim 1, wherein the daily dosage is an aqueous ophthalmicsolution free of a chelating agent, comprising: (a) about 0.5% (w/v) toabout 2% (w/v) of phentolamine mesylate; (b) about 3% (w/v) to about 5%(w/v) of mannitol; (c) about 2 mM to about 4 mM of sodium acetate; and(d) water; wherein the solution has a pH in the range of 4.6 to 5.2 anddoes not contain a chelating agent.
 12. The method of claim 1, whereinthe daily dosage is an aqueous ophthalmic solution free of a chelatingagent, comprising: (a) about 0.5% (w/v) to about 1% (w/v) ofphentolamine mesylate; (b) about 4% mannitol; (c) about 3 mM sodiumacetate; and (d) water; wherein the solution has a pH in the range of4.6 to 5.2 and does not contain a chelating agent.
 13. The method ofclaim 1, wherein the daily dosage is administered within 1 hour of thepatient's bedtime.
 14. The method of claim 7, wherein the daily dosageis administered within 1 hour of the patient's bedtime.
 15. The methodof claim 1, wherein the aqueous ophthalmic solution comprises from about0.5% (w/v) to about 2% (w/v) of phentolamine mesylate.
 16. The method ofclaim 6, wherein the aqueous ophthalmic solution comprises from about0.5% (w/v) to about 2% (w/v) of phentolamine mesylate.
 17. The method ofclaim 7, wherein the aqueous ophthalmic solution comprises from about0.5% (w/v) to about 2% (w/v) of phentolamine mesylate.
 18. The method ofclaim 13, wherein the aqueous ophthalmic solution comprises from about0.5% (w/v) to about 2% (w/v) of phentolamine mesylate.
 19. The method ofclaim 1, wherein the aqueous ophthalmic solution comprises: (a) about0.5% (w/v) to about 2% (w/v) of phentolamine mesylate; (b) about 1%(w/v) to about 6% (w/v) of at least one polyol compound selected fromthe group consisting of mannitol, glycerol, and propylene glycol; (c)about 1 mM to about 6 mM of an alkali metal acetate; and (d) water;wherein the solution has a pH in the range of 4.5 to 5.5 and does notcontain any additional material that is a chelating agent.
 20. Themethod of claim 13, wherein the aqueous ophthalmic solution comprises:(a) about 0.5% (w/v) to about 2% (w/v) of phentolamine mesylate; (b)about 1% (w/v) to about 6% (w/v) of at least one polyol compoundselected from the group consisting of mannitol, glycerol, and propyleneglycol; (c) about 1 mM to about 6 mM of an alkali metal acetate; and (d)water; wherein the solution has a pH in the range of 4.5 to 5.5 and doesnot contain any additional material that is a chelating agent.
 21. Themethod of claim 15, wherein within 8 hours after administration ofphentolamine mesylate to the patient's eye, the amount of eye rednessreturns to the baseline amount of eye redness present in the patient'seye prior to said administration of phentolamine mesylate.
 22. A methodfor improving visual performance, comprising daily ophthalmicadministration of an aqueous ophthalmic solution comprising about 1%(w/v) phentolamine mesylate to an eye of a patient at or near thebedtime of the patient, to thereby improve visual performance, whereinthe method is characterized by: the patient experiences an increase ineye redness of no more than one grade measured using the CCLRU RednessGrading Scale during the patient's waking hours compared to thepatient's level of eye redness without receiving said aqueous ophthalmicsolution; the aqueous ophthalmic solution is administered to the eye ofthe patient in an amount sufficient to provide improved visualperformance for at least twenty hours; the aqueous ophthalmic solutionis administered as an eye drop to the eye of the patient; and within 8hours after administration of phentolamine mesylate to the patient'seye, the amount of eye redness returns to the baseline amount of eyeredness present in the patient's eye prior to said administration ofphentolamine mesylate.
 23. The method of claim 22, wherein the aqueousophthalmic solution is administered within 1 hour of the patient'sbedtime.
 24. The method of claim 22, wherein the aqueous ophthalmicsolution comprises 1% (w/v) phentolamine mesylate.
 25. The method ofclaim 23, wherein the aqueous ophthalmic solution comprises 1% (w/v)phentolamine mesylate.
 26. The method of claim 22, wherein the aqueousophthalmic solution is administered as one eye drop to the eye of thepatient near the bedtime of the patient.
 27. The method of claim 24,wherein the aqueous ophthalmic solution is administered as one eye dropto the eye of the patient near the bedtime of the patient.